SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Cinacalcet Zentiva 90 mg film-coated tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Cinacalcet Zentiva 90 mg film-coated tablets

Each tablet contains 90 mg of cinacalcet (as hydrochloride).

Excipient with known effect:

Cinacalcet Zentiva 90 mg film-coated tablets

Each tablet contains 186.05 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Cinacalcet Zentiva 90 mg film-coated tablets

Light green, oval, 9.16 mm x 14.48 mm film-coated tablet marked “90” on one side and plain on the other

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage

renal disease (ESRD) on maintenance dialysis therapy.

Cinacalcet Zentiva m ay be used as part of a t herapeutic r egimen i ncluding

phosphate binders and/or Vitamin D sterols, as appropriate (see section 5.1).

Reduction of hypercalcaemia in 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 parath yroidectomy is not cl inically approp riate or i s 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. Cinacalcet Zentiva should be titrat ed every 2-4 weeks to a maximum dose of 18 0 mg once daily to achieve a target parathyroid hormone (PTH) in dial ysis 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 leas t 12 hours after dosing with Cinaca lcet Zentiva. Re ference sho uld be ma de to c urrent tre atment guidelines. PTH should be measured 1-4 weeks after initiation or dose adjustment of Cinacalcet Zentiva. PTH should b e monitored appr oximately every 1- 3 months du ring maintenance. Either the intact PTH (iPTH) or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with Cinacalcet Zentiva does not alter the relationship between iPTH and biPTH.

During dose titration, serum calcium lev els should be monitored f requently, and within 1 week of initiation or dose adjustment of Cinacalcet Zentiva. Once the maintenance dose has been established, serum calcium should be measured approximately monthl y. If serum ca lcium le vels de crease be low the no rmal range, appropriate steps should be taken, including adjustment of concomitant therapy (see section 4.4).

Children and adolescents

Cinacalcet Zentiva is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 4.4).

Parathyroid carcinoma and primary hyperparathyroidism

Adults and elderly (> 65 years)

The rec ommended starting dos e of Cinac alcet Zentiva for a dults is 30 mg twice per da y. The dose of Cinacalcet Zentiva s hould be titrated ever y 2-4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice dail y, and 90 mg three or f our times dail y as necess ary to re duce serum calcium concentr ation 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 w ithin 1 week aft er initiation or dose adjustment of C inacalcet Z entiva. Once m aintenance dos e l evels hav e b een established, serum calcium should be measured every 2-3 months.

After titration to the m aximum dose of Cinacalcet Zentiva, serum calcium should be periodicall y monitored; if clin ically relevant redu ctions in s erum calcium ar e not m aintained, di scontinuation of Cinacalcet Zentiva t herapy should be considered (see section 5.1).

Children and adolescents

Cinacalcet Zentiva is not indicated for use in children and adolescents due to a lack of data on safety and efficacy (see section 4.4).

Hepatic impairment

No chan ge in starting d ose is ne cessary. Cinac alcet Zentiva should be u sed with c aution in pa tients with mode rate to se vere he patic impa irment a nd treatment should be closel y monitore d durin g dose titrati on and continued treatment (see sections 4.4 and 5.2).

Method of administration

For oral use.

It is recommended that Cinacalcet Zentiva be taken with food or shortly after a meal as studies have shown that bioavailability of cinacalcet is increased when taken with food (s ee se ction 5.2). T ablets shou ld be tak en whol e and not divided.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Serum calcium

Cinacalcet treatment should not be initia ted in patients with a serum c alcium (corrected for albumin) below the lower limit of the normal range.

Life t hreatening ev ents and fat al out comes ass ociated wi th h ypocalcaemia have be en repo rted in a dult and paed iatric p atients tre ated with c inacalcet. Manifestations of h ypocalcaemia m ay i nclude par aesthesias, m yalgias, cramping, tetany and convulsions.

Decreases in se rum c alcium can also p rolong the QT inte rval, pot entially resulting in ventricul ar 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 s yndrome or patients r eceiving 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 c alcium should be measured within 1 w eek after initiation or do se adjustment of c inacalcet. Once the maintenan ce d ose has been established, serum calcium should be measured approximately monthly.

In the event that serum calcium levels fall below 8.4 mg/dl (2.1 mmol/l) and/or symptoms of h    ypocalcaemia o ccur the following ma nagement is

recommended:

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 s ymptoms of hypocalcaemia despite a ttempts to increase serum calcium	Reduce or withhold dose of cinacalcet.
< 7.5 mg /dl (1.9 mmol/l) or persistent symptoms of hypocalcemia and Vit amin D cannot be increased	Withhold admin istration of cinacalc et until serum calcium l evels reach 8.0 mg/dl (2.0 mmol/l) and/ or s ymptoms of hypocalcaemia have resolved. Treatment should be reinitiated using the next lowest dose of cinacalcet.

In C KD pat ients rec eiving di alysis who wer e adm mistered ci nacalcet, approximately 30% of p atients had at least one serum calcium value less than

7.5 mg/dl (1.9 mmol/l).

Cinacalcet is not indicated for C KD patients not on di alysis. Investigational studies have shown t hat CKD patients not on dialysis treated with cinacalcet have an incr eased risk for h ypocalcaemia (serum calcium levels < 8.4 mg /dl [2.1mmol/l]) com pared wi th ci nacalcet-treated C KD pat ients on di alysis, which may b e due to lowe r ba seline calcium l evels and/or the pres ence of residual kidney function.

Seizures

In clinical studies seizures were observed in 1.4% of cinacalcet treated patients and 0.7% of placebo-t    reated patients. W hile the basis for the reported

difference in seizure rate is not clear, the threshold for seiz ures is lowered b y significant reductions in serum calcium levels.

Hypotension and/or worsening heart failure

In post-marke ting sa fety surve illance, isola ted, idios yncratic c ases of hypotension

and/or worsening heart failure hav e b een reported in pa tients with impa ired cardiac function, in whi ch a c ausal re lationship to cinacalc et could not be completely e xcluded a nd may be me diated b y reductions in serum calcium levels. Clinical trial data showed hypotension occurred in 7% o f cinacalcet-treated patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving cinacalcet or placebo.

General

Adynamic bone disease may develop if PTH levels are chronically suppressed below

approximately 1.5 -times the upper limit of nor mal w ith the i PTH assay . If PTH levels decrease below the recommended target range in p atients treated with cinacalc et, the dos e of cina calcet and/or v itamin D sterols should be reduced or therapy discontinued.

Testosterone levels

Testosterone le vels a re often be low th e norma l ra nge in pa tients with end-stage renal disease.

In a clinical stud y of ESRD patients on dial ysis, fre e testosterone levels decreased by a median of 31.3% in th e cinacalcet-treated p atients an d by 16.3% in the placebo-tre ated patients af ter 6 months of treatment. An open-label ex tension of this s tudy showed no further reductions in fre e and t otal testosterone con centrations over a pe riod of 3 years i n ci nacalcet-treated patients.

The clinical significance of these reductions in serum testosterone is unknown. Hepatic impairment

Due to the potential for 2- 4 fold higher plasma levels of cinacalcet in patients with mode rate to se vere he patic imp airment (C hild-Pugh classification), cinacalcet should be use d with caution in these p atients and tre atment should be closely monitored (see sections 4.2 and 5.2).

Lactose monohydrate

Patients with ra re he reditary probl ems of g alactose intolerance, the Lapp lactase d eficiency o r glucose-galactose m alabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medications on cinacalcet

Cinacalcet is metabolised in part by the enzyme CYP3A4. Co-administration of 200 m g bid k etoconazole, a stron g inhibit or of CYP3A4, caused an approximate 2-fold increase in cinacalcet levels. Dose adjustment of cinacalcet may be required if a p atient re ceiving cin acalcet initiates or disconti nues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g. rifampicin) of this enzyme (see section 4.4).

In vitro data indic ate tha t c inacalcet is in pa rt me tabolised b y CYP1 A2. Smoking induces CYP1A2; the clearance of cinacalcet was observed to be 3638% higher in smokers than non smokers.

The effe ct of C YP1A2 inhibitors (e .g. fluv oxamine, ciproflox acin) on cinacalcet pl asma l evels has not be en st udied. Dose adj ustment m ay be necessary if a patient starts or stops smoking or whe n concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

Calcium carbonate

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

Sevelamer

Co-administration of sevelamer (2,400 m g 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 medications

Medicinal products me tabolised by the enz yme P450 2D6 (CYP2 D6): Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments of concomitant medicinal products ma y be required when cinacalcet is administered with individually titra ted, narrow th erapeutic in dex substa nces tha t a re predominantly m etabolised by C YP2D6 (e. g. fl ecainide, propa fenone, metoprolol, desipramine, nortriptyline, clomipramine) (see section 4.4).

Desipramine

Concurrent administrati on of 90 mg cinacalcet once d aily with 50 mg desipramine, a tric yclic a ntidepressant me tabolised prima rily by CYP2D6, significantly incr eased d esipramine ex posure 3.6 -fold (90% C I 3.0, 4.4) in CYP2D6 extensive metabolisers.

Warfarin

Multiple ora l dose s of c inacalcet did not affe ct the pha rmacokinetics or pharmacodynamics (as measured by prothrombin time and clotting factor VII) of warfarin.

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

Midazolam

Co-administration of ci nacalcet (90 m g) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, did not alter the pharm acokinetics of midaz olam. These data suggest that cinac alcet would not affe ct the pharmacokinetics of th ose classes of m edicines t hat are m etabolized b y CYP3A4 and CYP3A5 , such as cer tain imm unosuppressants, including cyclosporine and tacrolimus.

4.6 Fertility, pregnancy and lactation

Fertility

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

Pregnancy

There are no clinical d ata from t he use of cinacalcet i n pr egnant wo men. Animal studies do not indicate dire ct harmful effe cts with resp ect to pregnancy, parturition or postnatal development.

No e mbryonal/foetal to xicities we re se en in studie s in pre gnant ra ts a nd rabbits, with the exception of decr eased foetal body weights in rats, at doses associated with maternal toxicities (see section 5.3). Cinacalcet 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 i n human milk. Cinacalcet is excreted in the milk of lactating rats with a high milk to plasma ratio. Following careful benefit/r isk assessment, a d ecision should be mad e to discontinue either breast-feeding or treatment with cinacalcet.

4.7 Effects on ability to drive and use machines

No studies on the e ffects on the ability to drive and use machines have been performed. However, certain adverse reactions may affect the ability to drive and use machines (see section 4.8).

4.8 Undesirable effects

a) Summary of the safety profile

Secondary h yperparathyroidism, parathyroid carcinoma and pri mary hyperparathyroidism

Based on avai lable da ta from pat ients recei ving ci nacalcet i n pl acebo controlled studies and single-arm studies the most commonly reported adverse reactions w ere n ausea and vomiting . Na usea and vomiting were mild to moderate in se verity and transient in na ture in the majority of pa tients.

Discontinuation of therapy as a result of undesirable effects was mainly due to nausea and vomiting.

b) Tabulated list of adverse reactions

Adverse reactions, con sidered at l east possi bly attributable to ci nacalcet treatment in the pla cebo controlled studies and single-arm studies b ased on best-evidence a ssessment of c ausality are liste d be low using the following convention: very common (> 1/10); common (> 1/100 to <1/10); un common (> 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 postmarketing experience are:

MedDRA System Organ Class	Frequency	Adverse drug reactions
Immune system disorders	Common H	ypersensitivity reactions
Metabolism and nutrition disorders	Common Ano	■e xia, decreased appetite
Nervous system disorders	Common Seiz	ures1, dizziness, paraesthesia, headache
Cardiac disorders	Not known*	Worsening heart failure1, QT prolongation and ventricular arrhythmia secondary to hypocalcaemia1
Vascular disorders	Common	Hypotension
Respiratory, thoracic and mediastinal disorders	Common	Upper respiratory infection, dyspnoea, cough
Gastrointestinal disorders	Very common	Nausea, vomiting,
	Common D	yspepsia, diarrhoea, abdominal pain, abdominal pain - upper, constipation
Skin and subcutaneous tissue disorders	Common Ra	sh
Musculoskeletal and connective tissue disorders	Common	Myalgia, muscle spasms, back pain
General disorders and administration site conditions	Common Asth	e nia
Investigations Common		Hypocalcaemia1, hyperkalaemia,

reduced testosterone levels¹

¹ see section 4.4 * see section c

c) Description of selected adverse reactions Hypersensitivity reactions

Hypersensitivity r eactions including an gioedema and urticaria hav e been identified durin g post marketing use of cinacalcet. The fr equencies of the individual preferr ed ter ms including angioedema and urticaria c annot be estimated from available data.

Hypotension and/or worsening heart failure

There hav e been r eports of idios yncratic c ases of h ypotension an d/or worsening he art f ailure in ci nacalcet-treated p atients wi th i mpaired c ardiac function in post-ma rketing safe ty surv eillance, the fre quencies of w hich cannot be estimated from available data.

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been i dentified duri ng p ost-marketing use of cinacalcet, t he frequencies of which cannot be estimated from available data (see section 4.4).

d) Paediatric population

Cinacalcet i s not i ndicated for use i n p aediatric pat ients. The sa fety and efficacy of cinacalcet in the paediatric population have not been established. A fatal outc ome wa s reported in a p aediatric c linical tria l p atient with seve re hypocalcaemia (see section 4.4).

Reporting of suspected adverse reactions

Reporting susp ected ad verse reactions af ter authorisation of the m edicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal p roduct. Healthca re professionals are asked to report any suspected advers e rea ctions vi a The Yel lowcard R eporting S cheme: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Doses titra ted up to 30 0 mg onc e da ily h ave been safe ly administered to patients receiving dialysis.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Mechanism of action

The calcium sensing receptor on the surface of the chief cell of the parathyroid gland

is the principal regulator of PTH s ecretion. Cinacalcet is a calcimimetic agent which directly lowers PTH le vels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The re duction in PTH i s associated with a concomitant decrease in serum calcium levels.

Reductions in PTH levels correlate with cinacalcet concentration.

After st eady st ate i s rea ched, serum cal cium co ncentrations rem ain con stant over the dosing interval.

Secondary hyperparathyroidism

Three, 6-month, double-blind, placebo-c ontrolled clinical studies w ere conducted in ESRD p atients with uncontrolled seconda ry HPT receiving dialysis (n = 1,136). Demog raphic and baseline char acteristics were representative of the dia lysis patient population with secondar y HPT. Mean baseline iPTH con centrations acro ss the 3 studi es wer e 733 and 683 p g/ml (77.8 and 72.4 pmol/l) for the cinacalcet and placebo groups, respectively. 66% of patients were r eceiving vitamin D sterols at stud y entry, and > 90% were receiving phosphate binders.

Significant redu ctions in iPTH, se rum calcium-phosphorus product (Ca* P), calcium,

and phosphorus w ere o bserved in th e cina calcet treat ed patients compared with placebo-treated patients receiving standard of care, and t he results were consistent across the 3 s tudies. In each of the studies, the primar y endpoint (proportion of p atients with an iPTH < 250 p g/ml ( < 26.5 pmol/l)) was achieved by 41%, 46 %, and 35% of patie nts receiving cinacalcet, compared with 4%, 7%, and 6% o f patients re ceiving placebo. Approximately 60% of cinacalcet-treated patients achieved a > 30% reduction in iPTH levels, and this effect was consistent across the spectrum of ba seline iPTH levels. The mean reductions in serum Ca*P, calcium, and phosphorus were 14%, 7% and 8%, respectively.

Reductions in iPTH an d Ca*P w ere ma intained for up to 12 months of treatment. Cinacalc et decreas ed iP TH and Ca*P , calcium and phosphorus levels regardless of baseline iPTH or Ca*P level, dialysis modality (PD versus HD), duration of dial ysis, and whethe r or n ot vita min D ste rols were administered.

Reductions in PTH w ere associated with non-significant reductions of bone metabolism markers (bo ne specific alk aline phosphatase, N-telop eptide, bone turnover and bone fibrosis). In post-hoc analyses of pooled data from 6 and 12 months clinical studies , Kaplan-M eier estimates of bone fractu re and parathyroidectomy were lower in the cina calcet g roup c ompared with the control group.

Investigational studies in patient s with CKD and seconda ry HPT not undergoing dial ysis indicated that cina calcet reduced PTH levels to a similar extent as in patients w ith ESRD a nd seconda ry HPT re ceiving dial ysis. However, efficacy, safety, optimal doses and treatment targets have not been established in tre atment of pre dialytic re nal fa ilure pa tients. The se stu dies show that CKD p atients not under going di alysis treated with cina calcet have an i ncreased ri sk for h ypocalcaemia co mpared wi th ci nacalcet-treated E SRD patients receiving dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) was a randomized, double-blind clinical study evaluatin g cinac alcet HCl vs. placebo fo r th e redu ction of th e risk of a ll-cause mort ality and cardiovascular ev ents in 3,883 patie nts with secondary HPT and C KD receiving di alysis. The st udy di d not m eet i ts pri mary obj ective of demonstrating a r eduction in risk of a ll-cause morta lity or c ardiovascular events including m yocardial infar ction, hospitaliz ation for unstable an gina, heart failure or p eripheral vascular event ( HR 0.93; 95% C I:0.85, 1.02; p = 0.112). After adjusting for baseline characteristics in a secondary analysis, the HR for the primary composite endpoint was 0.88; 95% CI: 0.79, 0.97.

Parathyroid carcinoma and primary hyperparathyroidism In one study,46 patients (29 with parathyroid carcinoma and 17 with primary HPT and severe h ypercaelcemia (who ha d failed or had cont raindications to parathyroidectomy) received cinacal cet for up to 3 years (m ean of 328 da ys for patients with p arathyroid carcinoma and mean of 347 da ys for p atients with primary HPT). Cinacalcet was administered at doses ranging from 30 mg twice daily to 90 mg four times daily. The primary endpoint of the study was a reduction of serum calcium of > 1 m g/dl (> 0.2 5 mmol/l). In patients with parathyroid carcinoma, mean serum calcium declined from 14.1    12.4 mg/dl

(3.5-3.1 mmol/l), while in patients with primary HPT, serum calcium levels declined from 12.7-10.4 mg/dl (3.2-2.6 mmol/l). Eighteen of 29 patients (62%) with parathyroid carcinoma and 15 of 17 subjects (88%) with primar y HPT achieved a reduction in serum calcium of > 1 mg/dl (> 0.25 mmol/l).

In a 28 week placebo-controlled study, 67 patients with primary HPT who met criteria for parathyroidectomy 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 wh o were unabl e to under go parathyroidectomy were included.

Cinacalcet was initiated at a dose of 30 mg twice daily and titrated to maintain a c orrected tota l s erum c alcium concentration within the norma l range. A significantly hi gher per centage of ci nacalcet t reated pat ients achi eved m ean 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 conc entration, when compa red with t he placebo treat ed pati ents (75.8% versus 0% and 84.8% versus 5.9% respectively).

5.2 Pharmacokinetic properties

Absorption

After ora l a dministration of c inacalcet, max imum pla sma c inacalcet concentration is achieved in approximately 2-6 hours. Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has been estimated to be about 20-25%. Admin istration of cinacalcet with food results in an a pproximate 50- 80 % inc rease in c inacalcet bioa vailability. Increases in plasma cinacalcet conc entration are similar, reg ardless of the fat content of the meal. At doses abov e 200 m g, the absorption w as saturated probably due to poor solubility.

Distribution

The volume of distribution is hig h (approximately 1,000 l), indic ating extensive distribution. Cinacalcet is approx imately 97 % bound to plasma proteins and distributes minimally into red blood cells.

After absorption, cinacalcet concentrations decline in a biphasic f ashion with an initial half-life of approximately 6 hours and a terminal half-life of 30    40

h. Steady state levels of cinacalcet are achi eved within 7 days with minimal accumulation. The pharmacokinetics of cinacalcet does not change over time.

Biotransformation

Cinacalcet is metabolise d by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the contribution of CYP1A2 ha s not been characterised clinically). The major circulating metabolites are inactive.

Based on i n vi tro dat a, ci nacalcet i s a st rong i nhibitor of C YP2D6, but i s neither an inhibitor of other CYP enzymes at concent rations achi eved clinically, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 nor an inducer of CYP1A2, CYP2C19 and CYP3A4.

Elimination

After a dministration of a 75 mg radiolabelled dose to health y volunte ers, cinacalcet was rapidly and extensively metabolised by oxidation followed by conjugation. Renal ex cretion of metabo lites was the p revalent route of elimination of radioactivity. Approximately 80% of the dose was recovered in the urine and 15% in the faeces.

Linearity/non-linearity

The AUC and C max of ci nacalcet i ncrease approximately l inearly over t he dose range of 30-180mg once daily.

Pharmacokinetic/pharmacodynamic relationship(s)

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

Special populations

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, and severe renal insufficiency, and those on haemodialysis or peritoneal dialysis is comparable to that in healthy volunteers.

Hepatic insufficiency

Mild hepatic impairme nt did not notab ly affect t he ph armacokinetics of cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was approx imately 2-fol d hi gher i n subj ects wi th m oderate impairment a nd a pproximately 4-fold hi gher in subje cts with se vere impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with mode rate and severe hepatic impairment, respectively. Protein binding of cinacalcet is not aff ected by impaired hepatic function. Because doses are titrated for each subject based on safety and efficacy parameters, no additional dose adjustment is ne cessary for subjec ts with he patic impairment (see sections 4.2 and 4.4).

Gender

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

Paediatric population

The pharmacokinetics of cinacalcet have been studied in 12 paediatric patients (6-17 years) with CKD receiving dialysis following a single, oral, 15 mg dose. Mean AUC and Cmax values (23.5 (range 7.22-77.2) ng*h/ml and 7.26 (range 1.80-17.4) ng/ml, respectively) were within app roximately 30% of the m eans for AUC and Cmax values observed in a sin gle stud y in health y ad ults following a sing le 30 mg dose (33.6 (r ange 4.75-66.9) ng *h/ml and 5.42 (range 1.41-12.7) ng/ml, respectively). Due to the limited data in p aediatric subjects, the potential for hig her exposures in the lighter/younger relative to heavier/older paedi atric subj ects for a given d ose of cinac alcet c annot be excluded. The pharmacokinetics in paediatric subjects after multiple doses has not been studied.

Smoking

Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of CYP1A2- mediated metabolism. If a p atient stops or st arts smoking, cinacalcet plasma levels ma y change and dose adjustment ma y be necessary.

5.3 Preclinical safety data

Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4-times, on an AUC basis, the max imum human dose for secondary HPT (180 mg daily). The non-terato genic dose in rats wa s 4.4-tim es, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertility in males or females at ex posures up to 4 times a human dose of 180 m g/day (s afety margins in th e small population of patients administered a maximum clinical dose of 360 mg daily would be approximately half those given above).

In p regnant rats, the re were slig ht de creases in bod y weight and food consumption at the highest dose. Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia.

Cinacalcet has been shown to cross the placental barrier in rabbits.

Cinacalcet did not show an y genotoxic or carcinogenic potential. S afety margins from the tox icology studie s are sma ll due to the dos e-limiting hypocalcaemia obse rved in the a nimal mode ls. Cataracts a nd le ns opa cities were obse rved in the repeat dose rod ent tox icology a nd ca rcinogenicity studies, but were not 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 s erotonin transporter and KA TP channels were found to be 7- and 12-fold greater, respectively, than the EC50 for t he cal cium-sensing recept or obt ained und er t he sam e ex perimental conditions. The clinical relevan ce is unknown, however, the potential for cinacalcet to act on these secondary targets cannot be fully excluded.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Starch pregelatinised (maize) Silica, colloidal anhydrous Crospovidone (type A) Copovidone (K-28) Cellulose, microcrystalline Lactose monohydrate Maize starch Magnesium stearate

Coating

Opadry II 32K210001 green:

Lactose monohydrate Hypromellose 2910, 15 mPas Titanium dioxide (E171)

Triacetin

Indigo Carmine Aluminum lake (E132) Iron oxide yellow (E172)

Opadry II 85F19250 clear:

Polyvinyl alcohol Talc

Macrogol 3350 Polysorbate 80

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

PVC/ACLAR/PVC-Aluminuim foil blisters, paper folding box.

Pack sizes: 14, 28, 30, 84 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

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

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited One Onslow Street

Guildford Surrey GU1 4YS UK

Trading as: Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK.

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/076

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/03/2016

10    DATE OF REVISION OF THE TEXT

08/03/2016