MIMPARA 90mg tablets medication leaflet

Mimpara 30 mg film-coated tablets

Mimpara 60 mg film-coated tablets

Mimpara 90 mg film-coated tablets

Mimpara 30 mg film-coated tablets

Each tablet contains 30 mg cinacalcet (as hydrochloride).

Each tablet contains 2.74 mg of lactose.

Mimpara 60 mg film-coated tablets

Each tablet contains 60 mg cinacalcet (as hydrochloride).

Each tablet contains 5.47 mg of lactose.

Mimpara 90 mg film-coated tablets

Each tablet contains 90 mg cinacalcet (as hydrochloride).

Each tablet contains 8.21 mg of lactose.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Mimpara 30 mg film-coated tablets

Light green, oval (approximately 9.7 mm long and 6.0 mm wide), film-coated tablet marked “AMG”on one side and “30” on the other.

Mimpara 60 mg film-coated tablets

Light green, oval (approximately 12.2 mm long and 7.6 mm wide), film-coated tablet marked “AMG”on one side and “60” on the other.

Mimpara 90 mg film-coated tablets

Light green, oval (approximately 13.9 mm long and 8.7 mm wide), film-coated tablet marked “AMG”on one side and “90” on the other.

Secondary hyperparathyroidism

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

Treatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stagerenal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequatelycontrolled 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 Dsterols, 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 calciumlevels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is notclinically appropriate or is contraindicated.

Secondary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every2 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 madeto current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara. PTH should bemonitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) orbio-intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alterthe 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 limitof the normal range prior to administration of first dose of Mimpara (see section 4.4). The normalcalcium 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 ofinitiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serumcalcium should be measured approximately monthly. In the event that corrected serum calcium levelsfall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcaemia occur the followingmanagement is recommended:

Corrected Serum calcium level or clinical Recommendationssymptoms of hypocalcaemia< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL Calcium-containing phosphate binders, vitamin D(1.9 mmol/L), or in the presence of clinical sterols and/or adjustment of dialysis fluid calciumsymptoms of hypocalcaemia concentrations can be used to raise serum calciumaccording to clinical judgment.

< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL Reduce or withhold dose of Mimpara.

(1.9 mmol/L) or persistent symptoms ofhypocalcaemia despite attempts to increaseserum calcium≤ 7.5 mg/dL (1.9 mmol/L) or persistent Withhold administration of Mimpara until serumsymptoms of hypocalcaemia and Vitamin D calcium levels reach 8.0 mg/dL (2.0 mmol/L) and/orcannot be increased symptoms of hypocalcaemia have resolved.

Treatment should be reinitiated using the next lowestdose of Mimpara.

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

The recommended starting dose for children aged ≥ 3 years to < 18 years is ≤ 0.20 mg/kg once dailybased 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 increasedsequentially through available dose levels (see table 1) no more frequently than every 4 weeks. Thedose can be increased up to a maximum dose of 2.5 mg/kg/day, not to exceed a total daily dose of180 mg.

Table 1. Mimpara daily dose in paediatric patients

Available sequential dose

Patient dry weight (kg) Starting dose (mg)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, 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 bemeasured 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 lowerdose once the iPTH is > 150 pg/mL (15.9 pmol/L). If Mimpara treatment has been stopped formore 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 isrecommended. Serum calcium levels in paediatric patients should be maintained within the normalrange. 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 Dosing recommendationsclinical symptoms of hypocalcaemia

Corrected serum calcium is at or below Stop treatment with Mimpara.*age-specified lower limit of normalor Administer calcium supplements, calcium-containingif symptoms of hypocalcaemia occur, phosphate binders and/or vitamin D sterols, as clinicallyregardless of calcium level. indicated.

Corrected total serum calcium is above Restart at the next lower dose. If Mimpara treatment hasage-specified lower limit of normal, and been stopped for more than 14 days, restart at therecommended starting dose.

Symptoms of hypocalcaemia haveresolved. If patient was receiving the lowest dose (1 mg/day) priorto 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 secondaryhyperparathyroidism 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 inpatients. In patients who have discontinued etelcalcetide, Mimpara should not be initiated until at leastthree subsequent haemodialysis sessions have been completed, at which time serum calcium should bemeasured. Ensure serum calcium levels are within the normal range before Mimpara is initiated (seesections 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 Mimparashould 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 calciumconcentration to or below the upper limit of normal. The maximum dose used in clinical trials was90 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 to3 months. After titration to the maximum dose of Mimpara, serum calcium should be periodicallymonitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of

Mimpara therapy should be considered (see section 5.1).

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

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

For oral use.

Tablets should be taken whole and should not be chewed, crushed or divided.

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

Mimpara is also available as granules for paediatric use. Children who require doses lower than30 mg, or who are unable to swallow tablets should receive Mimpara granules.

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

Hypocalcaemia (see sections 4.2 and 4.4).

Serum calcium

Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in adultand paediatric patients treated with Mimpara. Manifestations of hypocalcaemia may includeparaesthesias, myalgias, cramping, tetany and convulsions. Decreases in serum calcium can alsoprolong the QT interval, potentially resulting in ventricular arrhythmia secondary to hypocalcaemia.

Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated withcinacalcet (see section 4.8). Caution is advised in patients with other risk factors for QT prolongationsuch as patients with known congenital long QT syndrome or patients receiving medicinal productsknown to cause QT prolongation.

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

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 patientshad at least one serum calcium value less than 7.5 mg/dL (1.9 mmol/L).

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 withstandard of care therapy, where serum calcium is in the upper range of, or above, the age-specifiedreference interval.

Closely monitor serum calcium levels (see section 4.2) and patient compliance during treatment withcinacalcet. 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 theability of the patient to comply with the recommendations to monitor and manage the risk ofhypocalcaemia.

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

CKD patients not on dialysis

Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown thatadult 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 ondialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidneyfunction.

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

Hypotension and/or worsening heart failure

Cases of hypotension and/or worsening heart failure have been reported in patients with impairedcardiac function, in which a causal relationship to cinacalcet could not be completely excluded andmay 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 lowerserum calcium. Closely monitor serum calcium (see section 4.5).

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

Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately1.5 times the upper limit of normal with the iPTH assay. If PTH levels decrease below therecommended target range in patients treated with Mimpara, the dose of Mimpara and/or vitamin Dsterols should be reduced or therapy discontinued.

Testosterone levels

Testosterone levels are often below the normal range in patients with end-stage renal disease. In aclinical study of adult ESRD patients on dialysis, free testosterone levels decreased by a median of31.3% in the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months oftreatment. An open-label extension of this study showed no further reductions in free and totaltestosterone concentrations over a period of 3 years in Mimpara-treated patients. The clinicalsignificance of these reductions in serum testosterone is unknown.

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption should not take this medicine.

Medicinal products known to reduce serum calcium

Concurrent administration of other medicinal products known to reduce serum calcium and Mimparamay result in an increased risk of hypocalcaemia (see section 4.4). Patients receiving Mimpara shouldnot 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 bidketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcetlevels. Dose adjustment of Mimpara may be required if a patient receiving Mimpara initiates ordiscontinues 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. Theeffect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has notbeen studied. Dose adjustment may be necessary if a patient starts or stops smoking or whenconcomitant 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 ofcinacalcet.

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 inhibitorof CYP2D6. Dose adjustments of concomitant medicinal products may be required when Mimpara isadministered with individually titrated, narrow therapeutic index substances that are predominantlymetabolised by CYP2D6 (e.g. flecainide, propafenone, metoprolol, desipramine, nortriptyline,clomipramine).

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

Dextromethorphan: Multiple doses of 50 mg cinacalcet increased the AUC of 30 mgdextromethorphan (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 ofauto-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 suggestthat cinacalcet would not affect the pharmacokinetics of those classes of medicines that aremetabolised by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporineand tacrolimus.

There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do notindicate direct harmful effects with respect to pregnancy, parturition or postnatal development. Noembryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception ofdecreased 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 thefoetus.

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

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

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

Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism

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

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

Cardiac disorders Not known* Worsening heart failure†

QT prolongation andventricular arrhythmiasecondary to hypocalcaemia†

Vascular disorders Common Hypotension

Respiratory, thoracic and mediastinal Common Upper respiratory infectiondisorders Dyspnoea

Cough

Gastrointestinal disorders Very common Nausea

Common Dyspepsia

Abdominal pain

Abdominal pain - upper

Skin and subcutaneous tissue disorders Common Rash

Musculoskeletal and connective tissue Common Myalgiadisorders Muscle spasms

Back pain

General disorders and administration Common Astheniasite conditions

Investigations Common Hypocalcaemia†

Reduced testosterone levels††see section 4.4

*see section “Description of selected adverse reactions”

Hypersensitivity reactions including angioedema and urticaria have been identified duringpost-marketing use of Mimpara. The frequencies of the individual preferred terms includingangioedema 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 incinacalcet-treated patients with impaired cardiac function in post-marketing safety surveillance, thefrequencies 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 duringpost-marketing use of Mimpara, the frequencies of which cannot be estimated from available data (seesection 4.4).

The safety of Mimpara for the treatment of secondary HPT in paediatric patients with ESRD receivingdialysis was evaluated in two randomised controlled studies and one single-arm study (seesection 5.1). Among all paediatric subjects exposed to cinacalcet in clinical studies a total of19 subjects (24.1%; 64.5 per 100 subject years) had at least one adverse event of hypocalcaemia. Afatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (seesection 4.4).

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

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.

Doses titrated up to 300 mg once daily have been administered to adult patients receiving dialysiswithout adverse outcome. A daily dose of 3.9 mg/kg was prescribed to a paediatric patient receivingdialysis 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 bemonitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic andsupportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment foroverdose.

Pharmacotherapeutic group: Calcium homeostasis, anti-parathyroid agents. ATC code: H05BX01.

The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principalregulator of PTH secretion. Cinacalcet is a calcimimetic agent which directly lowers PTH levels byincreasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in

PTH is associated with a concomitant decrease in serum calcium levels.

Reductions in PTH levels correlate with cinacalcet concentration.

After steady state is reached, serum calcium concentrations remain constant over the dosing interval.

Secondary hyperparathyroidism

Three, 6-month, double-blind, placebo-controlled clinical studies were conducted in ESRD patientswith uncontrolled secondary HPT receiving dialysis (n = 1,136). Demographic and baselinecharacteristics were representative of the dialysis patient population with secondary HPT. Meanbaseline iPTH concentrations across the 3 studies were 733 and 683 pg/mL (77.8 and 72.4 pmol/L) forthe cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols atstudy entry, and > 90% were receiving phosphate binders. Significant reductions in iPTH, serumcalcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in thecinacalcet-treated patients compared with placebo-treated patients receiving standard of care, and theresults were consistent across the 3 studies. In each of the studies, the primary endpoint (proportion ofpatients with an iPTH ≤ 250 pg/mL (≤ 26.5 pmol/L)) was achieved by 41%, 46%, and 35% of patientsreceiving cinacalcet, compared with 4%, 7%, and 6% of patients receiving placebo. Approximately60% of cinacalcet-treated patients achieved a ≥ 30% reduction in iPTH levels, and this effect wasconsistent across the spectrum of baseline iPTH levels. The mean reductions in serum Ca x P, calcium,and phosphorus were 14%, 7% and 8%, respectively.

Reductions in iPTH and Ca x P were maintained for up to 12 months of treatment. Cinacalcetdecreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x Plevel, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterolswere administered.

Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bonespecific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses ofpooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture andparathyroidectomy were lower in the cinacalcet group compared with the control group.

Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated thatcinacalcet reduced PTH levels to a similar extent as in patients with ESRD and secondary HPTreceiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not beenestablished in treatment of predialytic renal failure patients. These studies show that CKD patients notundergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared withcinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calciumlevels and/or the presence of residual kidney function.

EVOLVE (EValuation Of Cinacalcet Therapy to Lower CardioVascular Events) was a randomised,double-blind clinical study evaluating cinacalcet versus placebo for the reduction of the risk ofall-cause mortality and cardiovascular events in 3,883 patients with secondary HPT and CKDreceiving dialysis. The study did not meet its primary objective of demonstrating a reduction in risk ofall-cause mortality or cardiovascular events including myocardial infarction, hospitalisation forunstable angina, heart failure or peripheral vascular event (HR 0.93; 95% CI: 0.85, 1.02; p = 0.112).

After adjusting for baseline characteristics in a secondary analysis, the HR for the primary compositeendpoint was 0.88; 95% CI: 0.79, 0.97.

The efficacy and safety of cinacalcet 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.

Study 1 was a double-blind, placebo-controlled study in which 43 patients aged 6 to < 18 years wererandomised to receive either cinacalcet (n = 22) or placebo (n = 21). The study consisted of a 24-weekdose titration period followed by a 6-week efficacy assessment phase (EAP), and a 30-week open-label extension. The mean age at baseline was 13 (range 6 to 18) years. The majority of patients (91%)were using vitamin D sterols at baseline. The mean (SD) iPTH concentrations at baseline were757.1 (440.1) pg/mL for the cinacalcet group and 795.8 (537.9) pg/mL for the placebo group. Themean (SD) corrected total serum calcium concentrations at baseline were 9.9 (0.5) mg/dL for thecinacalcet group and 9.9 (0.6) mg/dL for the placebo group. The mean maximum daily dose ofcinacalcet was 1.0 mg/kg/day.

The percentage of patients who achieved the primary endpoint (≥ 30% reduction from baseline inmean plasma iPTH during the EAP; weeks 25 to 30) was 55% in the cinacalcet group and 19.0% inthe placebo group (p = 0.02). The mean serum calcium levels during the EAP were within the normalrange for the cinacalcet treatment group. This study was terminated early due to a fatality with severehypocalcaemia in the cinacalcet group (see section 4.8).

Study 2 was an open-label study in which 55 patients aged 6 to < 18 years (mean 13 years) wererandomised to receive either cinacalcet in addition to standard of care (SOC, n = 27) or SOC alone(n = 28). The majority of patients (75%) were using vitamin D sterols at baseline. The mean (SD)iPTH concentrations at baseline were 946 (635) pg/mL for the cinacalcet + SOC group and1228 (732) pg/mL for the SOC group. The mean (SD) corrected total serum calcium concentrations atbaseline were 9.8 (0.6) mg/dL for the cinacalcet + SOC group and 9.8 (0.6) mg/dL for the SOC group.

25 subjects received at least one dose of cinacalcet and the mean maximum daily dose of cinacalcetwas 0.55 mg/kg/day. The study did not meet its primary endpoint (≥ 30% reduction from baseline inmean plasma iPTH during the EAP; weeks 17 to 20). Reduction of ≥ 30% from baseline in meanplasma iPTH during the EAP was achieved by 22% of patients in the cinacalcet + SOC group and 32%of patients in the SOC group.

Study 3 was a 26-week, open-label, single-arm safety study in patients aged 8 months to < 6 years(mean age 3 years). Patients receiving concomitant medicinal products known to prolong the corrected

QT interval were excluded from the study. The mean dry weight at baseline was 12 kg. The startingdose of cinacalcet was 0.20 mg/kg. The majority of patients (89%) were using vitamin D sterols atbaseline.

Seventeen patients received at least one dose of cinacalcet and 11 completed at least 12 weeks oftreatment. None had corrected serum calcium < 8.4 mg/dL (2.1 mmol/L) for ages 2-5 years. iPTHconcentrations from baseline were reduced by ≥ 30% in 71% (12 out of 17) of patients in the study.

Parathyroid carcinoma and primary hyperparathyroidism

In one study, 46 adult patients (29 with parathyroid carcinoma and 17 with primary HPT and severehypercalcaemia who had failed or had contraindications to parathyroidectomy) received cinacalcet forup to 3 years (mean of 328 days for patients with parathyroid carcinoma and mean of 347 days forpatients with primary HPT). Cinacalcet was administered at doses ranging from 30 mg twice daily to90 mg four times daily. The primary endpoint of the study was a reduction of serum calcium of≥ 1 mg/dL (≥ 0.25 mmol/L). In patients with parathyroid carcinoma, mean serum calcium declinedfrom 14.1 mg/dL to 12.4 mg/dL (3.5 mmol/L to 3.1 mmol/L), while in patients with primary HPT,serum calcium levels declined from 12.7 mg/dL to 10.4 mg/dL (3.2 mmol/L to 2.6 mmol/L). Eighteen(18) of 29 patients (62%) with parathyroid carcinoma and 15 of 17 subjects (88%) with primary HPTachieved a reduction in serum calcium of ≥ 1 mg/dL (≥ 0.25 mmol/L).

In a 28 week placebo-controlled study, 67 adult patients with primary HPT who met criteria forparathyroidectomy on the basis of corrected total serum calcium (> 11.3 mg/dL (2.82 mmol/L) but≤ 12.5 mg/dL (3.12 mmol/L), but who were unable to undergo parathyroidectomy were included.

Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a corrected total serumcalcium concentration within the normal range. A significantly higher percentage of cinacalcet-treatedpatients achieved mean corrected total serum calcium concentration ≤ 10.3 mg/dL (2.57 mmol/L) and≥ 1 mg/dL (0.25 mmol/L) decrease from baseline in mean corrected total serum calcium concentration,when compared with the placebo-treated patients (75.8% versus 0% and 84.8% versus 5.9%respectively).

After oral administration of Mimpara, maximum plasma cinacalcet concentration is achieved inapproximately 2 to 6 hours. Based on between-study comparisons, the absolute bioavailability ofcinacalcet in fasted subjects has been estimated to be about 20-25%. Administration of Mimpara withfood results in an approximate 50-80% increase in cinacalcet bioavailability. Increases in plasmacinacalcet concentration are similar, regardless of the fat content of the meal.

At doses above 200 mg, the absorption was saturated probably due to poor solubility.

The volume of distribution is high (approximately 1,000 litres), indicating extensive distribution.

Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red bloodcells.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life ofapproximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state levels of cinacalcet areachieved within 7 days with minimal accumulation. The pharmacokinetics of cinacalcet does notchange over time.

Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (thecontribution of CYP1A2 has not been characterised clinically). The major circulating metabolites areinactive.

Based on in vitro data, cinacalcet is a strong inhibitor of CYP2D6, but is neither an inhibitor of other

CYP enzymes at concentrations achieved clinically, including CYP1A2, CYP2C8, CYP2C9,

CYP2C19, and CYP3A4 nor an inducer of CYP1A2, CYP2C19 and CYP3A4.

After administration of a 75 mg radiolabelled dose to healthy volunteers, cinacalcet was rapidly andextensively metabolised by oxidation followed by conjugation. Renal excretion of metabolites was theprevalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in theurine and 15% in the faeces.

The AUC and Cmax of cinacalcet increase approximately linearly over the dose range of 30 to 180 mgonce daily.

Soon after dosing, PTH begins to decrease until a nadir at approximately 2 to 6 hours post-dose,corresponding with cinacalcet Cmax. Thereafter, as cinacalcet levels begin to decline, PTH levelsincrease until 12 hours post-dose, and then PTH suppression remains approximately constant to theend of the once daily dosing interval. PTH levels in Mimpara clinical trials were measured at the endof the dosing interval.

Elderly: There are no clinically relevant differences due to age in the pharmacokinetics of cinacalcet.

Renal insufficiency: The pharmacokinetic profile of cinacalcet in patients with mild, moderate, andsevere renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that inhealthy volunteers.

Hepatic insufficiency: Mild hepatic impairment did not notably affect the pharmacokinetics ofcinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet wasapproximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher insubjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% inpatients with moderate and severe hepatic impairment, respectively. Protein binding of cinacalcet isnot affected by impaired hepatic function. Because doses are titrated for each subject based on safetyand efficacy parameters, no additional dose adjustment is necessary for subjects with hepaticimpairment (see sections 4.2 and 4.4).

Gender: Clearance of cinacalcet may be lower in women than in men. Because doses are titrated foreach subject, no additional dose adjustment is necessary based on gender.

Paediatric population: The pharmacokinetics of cinacalcet was studied in paediatric patients with

ESRD receiving dialysis aged 3 to 17 years of age. After single and multiple once daily oral doses ofcinacalcet, plasma cinacalcet concentrations (Cmax and AUC values after normalisation by dose andweight) were similar to those observed in adult patients.

A population pharmacokinetic analysis was performed to evaluate the effects of demographiccharacteristics. This analysis showed no significant impact of age, sex, race, body surface area, andbody weight on cinacalcet pharmacokinetics.

Smoking: Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of

CYP1A2-mediated metabolism. If a patient stops or starts smoking, cinacalcet plasma levels maychange and dose adjustment may be necessary.

Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4 times, on an AUC basis, themaximum human dose for secondary HPT (180 mg daily). The non-teratogenic dose in rats was4.4 times, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertilityin males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in thesmall population of patients administered a maximum clinical dose of 360 mg daily would beapproximately half those given above).

In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose.

Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia. Cinacalcethas been shown to cross the placental barrier in rabbits.

Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicologystudies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts andlens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but werenot observed in dogs or monkeys or in clinical studies where cataract formation was monitored.

Cataracts are known to occur in rodents as a result of hypocalcaemia.

In in vitro studies, IC50 values for the serotonin transporter and KATP channels were found to be 7 and12-fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the sameexperimental conditions. The clinical relevance is unknown, however, the potential for cinacalcet toact on these secondary targets cannot be fully excluded.

In toxicity studies in juvenile dogs, tremors secondary to decreased serum calcium, emesis, decreasedbody weight and body weight gain, decreased red cell mass, slight decreases in bone densitometryparameters, reversible widening of the growth plates of long bones, and histological lymphoid changes(restricted to the thoracic cavity and attributed to chronic emesis) were observed. All of these effectswere seen at a systemic exposure, on an AUC basis, approximately equivalent to the exposure inpatients at the maximum dose for secondary HPT.

Pre-gelatinised starch (maize)

Microcrystalline cellulose

Povidone

Crospovidone

Magnesium stearate

Colloidal anhydrous silica

Carnauba wax

Lactose monohydrate

Hypromellose

Titanium dioxide (E171)

Glycerol triacetate

FD&C Blue (E132)

Iron oxide yellow (E172)

Macrogol

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

Aclar/PVC/PVAc/Aluminium blister containing 14 tablets. Pack sizes of 14 tablets (1 blister), 28tablets (2 blisters) and 84 tablets (6 blisters) per carton.

HDPE bottle with a cotton coil, and a child-resistant polypropylene cap with an induction seal, packedinto a carton. Each bottle contains 30 tablets.

Not all pack sizes may be marketed.

No special requirements.

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

EU/1/04/292/001 - 30 mg carton with 14 tablets

EU/1/04/292/002 - 30 mg carton with 28 tablets

EU/1/04/292/003 - 30 mg carton with 84 tablets

EU/1/04/292/004 - 30 mg bottle with 30 tablets

EU/1/04/292/005 - 60 mg carton with 14 tablets

EU/1/04/292/006 - 60 mg carton with 28 tablets

EU/1/04/292/007 - 60 mg carton with 84 tablets

EU/1/04/292/008 - 60 mg bottle with 30 tablets

EU/1/04/292/009 - 90 mg carton with 14 tablets

EU/1/04/292/010 - 90 mg carton with 28 tablets

EU/1/04/292/011 - 90 mg carton with 84 tablets

EU/1/04/292/012 - 90 mg bottle with 30 tablets

Date of first authorisation: 22 October 2004

Date of latest renewal: 23 September 2009

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

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