Cinacalcet Devatis 60 mg Film-coated Tablet

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Cinacalcet hydrochloride 66.12 mg equivalent to cinacalcet 60 mg
Available from:
Devatis Limited
Dosage:
60 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Cinacalcet hydrochloride 66.12 mg equivalent to cinacalcet 60 mg Excipient: Colloidal silicon dioxide Crospovidone Magnesium stearate Microcrystalline cellulose Opadry Clear OY-29020 Purified water Sheffcoat green L TN 1264G49 Starch
Prescription type:
Prescription
Therapeutic indications:
May be used to treat the biochemical manifestations of secondary hyperparathyroidism in adult patients with end stage renal disease, receiving dialysis. Cinacalcet hydrochloride should be used as an adjunctive therapy.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PCTFE/Al blisters - 28 tablets - 36 months from date of manufacture stored no storage statement needed
Authorization number:
TT50-10242a
Authorization date:
2017-08-14

CINACALCET Devatis

30 mg/60 mg/90 mg Film Coated Tablets

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Version: V02/August 2019

NEW ZEALAND DATA SHEET

1. PRODUCT NAME

CINACALCET Devatis 30 mg, 60 mg & 90 mg Film-Coated Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Substance:

Each 30 mg tablet contains 33.06 mg of cinacalcet hydrochloride (equivalent to 30 mg cinacalcet).

Each 60 mg tablet contains 66.12 mg of cinacalcet hydrochloride (equivalent to 60 mg cinacalcet).

Each 90 mg tablet contains 99.18 mg of cinacalcet hydrochloride (equivalent to 90 mg cinacalcet).

Excipient with known effect:

Each 30 mg tablet contains 0.3 mg of lactose

Each 60 mg tablet contains 0.6 mg of lactose

Each 90 mg tablet contains 0.9 mg of lactose

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.

Light green, oval film-coated tablets, marked with “30”, “60” or “90” on one side respectively.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

CINACALCET

Devatis

used

treat

biochemical

manifestations

secondary

hyperparathyroidism in patients with end stage renal disease, receiving dialysis. CINACALCET Devatis

should be used as adjunctive therapy.

CINACALCET Devatis

indicated

for the

treatment of

hypercalcemia

patients

with

parathyroid

carcinoma.

CINACALCET Devatis may be used to treat the biochemical manifestations of primary hyperparathyroidism

in patients for whom parathyroidectomy is not a treatment option.

4.2 Dose and Method of Administration

Dose

Patients with End Stage Renal Disease Receiving Dialysis

CINACALCET Devatis reduces PTH while simultaneously lowering Ca×P, calcium and phosphorus levels

in patients receiving dialysis.

The recommended starting dose for adults is 30 mg once per day.

CINACALCET Devatis should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to

achieve a target PTH between 15.9 and 31.8 pmol/L (150-300 pg/mL).

In chronic kidney disease (CKD) patients, PTH levels should be assessed at least 12 hours after dosing with

cinacalcet.

During dose titration, serum calcium levels should be monitored frequently and if serum calcium levels

decrease below the normal range, appropriate steps should be taken to increase serum calcium levels (see

section 4.4).

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Parathyroid Carcinoma and Primary HPT for Whom Parathyroidectomy is not a Treatment Option

The recommended starting dose of CINACALCET Devatis for adults is 30 mg twice daily.

The dosage of CINACALCET Devatis 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

normalize serum calcium.

Special Populations

Elderly

Age does not alter the pharmacokinetics of cinacalcet; no dosage adjustment is required for geriatric patients.

Renal impairment

Renal impairment does not alter the pharmacokinetics of cinacalcet; no dosage adjustment is necessary for

renal impairment.

Hepatic impairment

Moderate to severe hepatic impairment (Child-Pugh classification) increases cinacalcet drug concentrations

by approximately 2 to 4 fold. In patients with moderate-severe hepatic impairment, PTH and serum calcium

concentrations should be closely monitored during dose titration of cinacalcet.

Pediatric population

CINACALCET Devatis is not indicated for use in children and adolescents due to a lack of data on safety

and efficacy (see section 4.4).

Method of administration

CINACALCET Devatis is administered orally. It is recommended that CINACALCET Devatis be taken with

food or shortly after a meal. Tablets should be taken whole and should not be divided.

4.3 Contraindications

CINACALCET Devatis is contraindicated in patients with hypersensitivity to any component(s) of this

product.

Cinacalcet treatment should not be initiated in patients with a serum calcium (corrected for albumin) below

the lower limit of the normal range.

4.4 Special warnings and precautions for use

Seizures

In clinical studies, seizures (primarily generalized or tonic-clonic) were observed in 1.4% (43/3049) of

cinacalcet-treated patients and 0.7% (5/687) of placebo-treated patients. While the basis for the reported

difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum

calcium levels.

Hypotension and/or Worsening Heart Failure

In post-marketing safety surveillance, isolated, idiosyncratic 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.

Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated patients, 12% of placebo-treated

patients, and heart failure occurred in 2% of patients receiving cinacalcet or placebo.

Adynamic Bone

In CKD patients receiving dialysis adynamic bone may develop if PTH levels are suppressed below 100

pg/mL (10.6 pmol/L). If PTH levels decrease below the recommended target range in patients treated with

cinacalcet, the dose of vitamin D sterols and/or cinacalcet should be reduced or therapy discontinued.

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Serum Calcium

Cinacalcet treatment should not be initiated in patients with CKD receiving dialysis if serum calcium is less

than 8.4 mg/dl [2.1 mmol/L].

Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in patients

treated with cinacalcet including in pediatric patients. Decreases in serum calcium can prolong the QT

interval, potentially resulting in ventricular arrhythmia. Cases of QT prolongation and ventricular arrhythmia

secondary to hypocalcaemia have been reported in patients treated with cinacalcet. Manifestations of

hypocalcaemia may also include paresthesias, myalgias, cramping, tetany, and seizures.

Since cinacalcet lowers serum calcium, patients should be monitored for the occurrence of hypocalcaemia.

Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet. Once the

maintenance dose has been established, serum calcium should be measured approximately monthly.

If serum calcium falls below 8.4 mg/dl but remains above 7.5 mg/dl, or if symptoms of hypocalcaemia occur,

calcium-containing phosphate binders and/or vitamin D sterols can be used to raise serum calcium. If

hypocalcaemia persists, reduce the dose or discontinue administration of cinacalcet. If serum calcium falls

below 7.5 mg/dl, or if symptoms of hypocalcaemia persist and the dose of vitamin D cannot be increased,

withhold administration of cinacalcet until serum calcium levels reach 8.0 mg/dl and/or symptoms of

hypocalcaemia have resolved. Treatment should be reinitiated using the next lowest dose of cinacalcet (see

section 4.2).

In CKD patients receiving dialysis who were administered cinacalcet, 29% of patients in the 6-month

registrational trials and 21% and 33% of patients (within the first 6 months and overall, respectively) in the

EVOLVE (Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events) clinical trial, had at least

one serum calcium value less than 7.5 mg/dl (1.88 mmol/L). Less than 1% of patients receiving dialysis both

in the group treated with cinacalcet and in the group treated with placebo permanently discontinued study

drug due to hypocalcemia in the registrational clinical trials. In the EVOLVE clinical trial, 1.1% of patients

in the cinacalcet group and 0.1% in the placebo group permanently discontinued study drug due to

hypocalcemia.

Cinacalcet is not indicated for CKD patients not receiving dialysis. Investigational studies have shown that

CKD patients not receiving dialysis treated with cinacalcet have an increased risk of hypocalcaemia (serum

calcium levels less than 8.4 mg/dl [2.1 mmol/L]) compared with cinacalcet treated CKD patients receiving

dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

Hepatic Insufficiency

Due to the potential for 2 to 4 times higher plasma levels of cinacalcet in patients with moderate to severe

hepatic impairment, physicians should closely monitor these patients when initiating cinacalcet (see section

5.2).

Testosterone Levels

Testosterone levels are often below the normal range in patients with end-stage renal disease. In a clinical

study of CKD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the cinacalcet

treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. The clinical

significance of these reductions in serum testosterone is unknown. An open label extension of this study

showed no further reductions in free and total testosterone concentrations over a period of 3 years in

cinacalcet-treated patients.

Neoplastic Events

In a randomized, double-blind, placebo-controlled clinical study of 3,883 dialysis patients, neoplastic events

were reported in 2.9 and 2.5 patients per 100 patient-years in cinacalcet and placebo treatment groups,

respectively. A causal relationship to cinacalcet has not been established.

Coadministration with Other Products

Administer cinacalcet with caution in patients receiving any other medications known to lower serum

calcium. Closely monitor serum calcium levels in patients receiving other medications known to lower serum

calcium.

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Laboratory Tests

Patients with CKD and Secondary Hyperparathyroidism

Serum calcium should be measured within 1 week and iPTH should be measured 1 to 4 weeks after initiation

or dose adjustment of cinacalcet. Once the maintenance dose has been established, serum calcium should be

measured approximately monthly, and PTH every 1 to 3 months (see section 4.2). Either the intact PTH

(iPTH) or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with cinacalcet does not

alter the relationship between iPTH and biPTH.

Patients

with

Parathyroid

Carcinoma

and

Patients

with

Primary

Hyperparathyroidism

for

Whom

Parathyroidectomy is Not a Treatment Option

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

maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months (see

section 4.2).

Interference with Laboratory and Diagnostic Tests

None known.

Pediatric population

The safety and efficacy of cinacalcet in pediatric patients have not been established. Cinacalcet is not

indicated for use in pediatric patients. A fatal outcome was reported in a pediatric clinical trial patient with

severe hypocalcaemia (see section 4.4, Serum Calcium).

Use in the Elderly

Of the 1136 patients enrolled in the cinacalcet phase 3 clinical program, 26% were over 65 years old, and 9%

were over 75 years old. No differences in the safety and efficacy of cinacalcet were observed in patients

greater or less than 65 years of age (see section 4.2, Elderly).

Lactose: This product contains trace amount of lactose. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicines and other forms of interaction

Effect of Cinacalcet on Other Drugs

Drugs metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) – cinacalcet is an inhibitor of CYP2D6.

Therefore, dose adjustments of concomitant medications may be required when cinacalcet is administered

with medications that are predominantly metabolized by this enzyme (eg, metoprolol) and particularly those

with a narrow therapeutic index (e.g., flecainide, vinblastine, thioridazine and most tricyclic antidepressants).

Desipramine:

Concurrent

administration

cinacalcet

with

desipramine,

tricyclic

antidepressant metabolized primarily by CYP2D6, increased desipramine exposure approximately 3.6 times

in CYP2D6 extensive metabolizers.

Amitriptyline: Co-administration of 25 mg or 100 mg cinacalcet with 50 mg amitriptyline, a tricyclic

antidepressant metabolized in part by CYP2D6, increased exposure to amitriptyline and its active metabolite

nortriptyline by approximately 20% in extensive metabolizers of CYP2D6 enzymes. Dose reductions of

amitriptyline may be required in some subjects receiving cinacalcet concurrently.

Drugs metabolized by other cytochrome P450 (CYP) enzymes - based on in vitro data, cinacalcet is not an

inhibitor of

other CYP enzymes at concentrations

achieved

clinically, including

CYP1A2,

CYP2C9,

CYP2C19, and CYP3A4.

Warfarin: Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics (as

CINACALCET Devatis

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measured by prothrombin time and the 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 drugs that are metabolized by CYP3A4 and

CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus.

Effect of Other Drugs on Cinacalcet

Cinacalcet

metabolized

multiple

cytochrome

P450 enzymes,

primarily

CYP3A4,

CYP1A2

CYP2D6, which limit the potential for other drugs to increase cinacalcet concentrations.

Ketoconazole: Cinacalcet is metabolized in part by the enzyme CYP3A4. Co-administration of ketoconazole,

strong

inhibitor

CYP3A4,

caused

approximate

2-fold

increase

cinacalcet

exposure.

Dose

adjustment of cinacalcet may be required if a patient receiving cinacalcet initiates or discontinues therapy

with a strong CYP3A4 inhibitor (eg, ketoconazole, erythromycin, itraconazole) or inducer (eg, rifampicin,

phenytoin, St. John’s Wort) of this enzyme.

Calcium carbonate: Co-administration of calcium carbonate (1500 mg) did not alter the pharmacokinetics of

cinacalcet.

Sevelamer HCl: Co-administration of sevelamer HCl (2400 mg tid) did not alter the pharmacokinetics of

cinacalcet.

Pantoprazole: Co-administration of pantoprazole (2400 mg) did not alter the pharmacokinetics of cinacalcet.

4.6 Fertility, Pregnancy and Lactation

General advice: Pregnancy Category: B3*

Pregnancy

Cinacalcet crossed the placental barrier in rabbits; fetal plasma cinacalcet concentrations were about 10–13%

of the maternal plasma concentrations. There was no evidence of teratogenicity in rats or rabbits. Fetal body

weights were decreased in rats at 50 mg/kg/day PO (approximately 2 times the clinical exposure at the

MRCD, based on AUC) and increased incidences of unossified sternebrae occurred in rats at exposures 0.1 –

2 times the clinical exposure, with maternal toxicity.

There are no adequate and well-controlled studies of cinacalcet in pregnant women. Because animal

reproduction studies are not always predictive of human response, cinacalcet should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

*Drugs which have been taken by only a limited number of pregnant women and women of childbearing age,

without an increase in the frequency of malformation or other direct or indirect harmful effects on the human

fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal

damage, the significance of which is considered uncertain in humans.

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. Oral administration of cinacalcet to female rats during gestation and

lactation at doses of 25 mg/kg/day and above (exposures at and above ≥1.5 times the clinical exposure at the

MRCD, based on AUC) was associated with increases in neonatal loss and reduced body weight gain of

suckling rats.

Considering the rat study findings and because many drugs are excreted in breast milk, a decision should be

CINACALCET Devatis

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made to discontinue nursing or discontinue cinacalcet, taking into account the importance of cinacalcet to the

mother.

Fertility

Cinacalcet did not impair mating or fertility in rats at oral doses up to 75 mg/kg/day, with systemic exposures

up to 2 times human exposure at the maximum recommended clinical dose (MRCD), based on AUC.

Studies in monkeys showed that cinacalcet depressed serum testosterone concentrations by 70-90% at oral

doses 5-100 mg/kg/day, corresponding to systemic exposures 0.1-1 times the clinical exposure, on an AUC

basis, at the MRCD of 360 mg/day. The highest dose also resulted in a 42% reduction in testicular weights.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive or operate machinery have been observed.

4.8 Undesirable effects

a) Summary of the safety profile

Studies were conducted in patients with CKD receiving dialysis, and in patients with parathyroid carcinoma

or primary HPT for whom parathyroidectomy is not a treatment option. Cinacalcet was safe and generally

well tolerated. However, nausea and vomiting are very common adverse reactions.

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

In 3 double-blind placebo-controlled clinical trials, 1126 CKD patients on dialysis received study drug (656

cinacalcet, 470 placebo) for up to 6 months. Adverse events reported during the studies were typical for the

dialysis patient population. The most frequently reported adverse events (incidence of at least 5% in the

cinacalcet group) are provided in Table 1. The most frequently reported events in the cinacalcet group were

nausea and vomiting which were generally mild to moderate in severity, brief in duration, and infrequently

led to discontinuation of study drug. Rash and hypocalcaemia have been observed.

Seizures were observed in 1.4% (13/910) of cinacalcet-treated patients and 0.7% (5/641) of placebo-treated

patients across all completed placebo controlled trials.

The incidence of serious adverse events (29 % vs. 31%) and deaths (2% vs. 3%) was similar in the cinacalcet

and placebo groups, respectively.

12-Month Experience with Cinacalcet

Two hundred and sixty-six patients from the 2 pivotal phase 3 studies continued to receive cinacalcet or

placebo treatment in a 6-month double-blind extension study (12-month total treatment duration). The

incidence and nature of adverse events in this study were similar in the 2 treatment groups, and comparable

to those observed in the pivotal phase 3 studies.

Parathyroid Carcinoma and Primary HPT for Whom Parathyroidectomy is not a Treatment Option

Overall, the safety profile in patients with parathyroid carcinoma or intractable (failed or contraindicated to

surgery) primary HPT was similar to that seen in patients with CKD and secondary HPT; the most frequent

adverse events in this patient group were nausea and vomiting.

Summary of the Safety of Cinacalcet in Subjects with Primary HPT

The safety profile of cinacalcet was similar across the 5 studies in primary HPT. Overall, common adverse

events observed in these studies included gastrointestinal events (nausea, vomiting, abdominal pain),

headache, paresthesia, anxiety, asthenia, dizziness, and arthralgia. Most adverse events were mild to

moderate in severity. The most common event considered related to cinacalcet was nausea, which was also

the most common adverse event leading to withdrawal.

The safety profile of cinacalcet in this subject population was generally consistent with that in subjects with

CKD and no unique safety concern was identified for cinacalcet in the treatment of primary HPT.

Seizures were observed in 0.7% (1/140) of cinacalcet-treated patients and 0.0% (0/46) of placebo treated

patients in all clinical studies.

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b) Tabulated summary of adverse reactions

Table 1 Adverse Reactions in Clinical Trials in Secondary Hyperparathyroidism in Patients with

Chronic Kidney Disease Receiving Dialysis

System Organ Class

Very Common

Common

Gastrointestinal disorders

Nausea

Vomiting

Diarrhea

Musculoskeletal and connective tissue disorders

Myalgia

Nervous system disorders

Dizziness

Seizures

Vascular disorders

Hypertension

General disorders and administration site conditions

Asthenia

Pain chest, non cardiac

Psychiatric disorders

Anorexia

Infections and infestations

Access infection

Skin and subcutaneous tissue disorders

Rash

Metabolism and nutrition disorders

Hypocalcaemia

Very common: greater than 10%, common: between 1% and 10%

Table 2 Adverse Reactions in Clinical Trials in Patients with Parathyroid Carcinoma/Intractable

Primary HPT

System Organ Class

Very Common

Common

Gastrointestinal disorders

Nausea

Vomiting

Constipation

Nervous system disorders

Paresthesia

Headache

General disorders and administration site conditions

Fatigue

Asthenia

Injury, poisoning and procedural complications

Fracture

Metabolism and nutrition disorders

Hypercalcemia

Dehydration

Hypocalcemia

Psychiatric disorders

Anorexia

Depression

Blood and lymphatic system disorders

Anemia

Musculoskeletal and connective tissue disorders

Arthralgia

Pain limb

Infections and infestations

Infection upper respiratory

Very common: greater than 10%, common: between 1% and 10%

Post Marketing Data

Spontaneous post marketing reports have been received describing diarrhea, myalgia, rash, seizures and

hypersensitivity

reactions,

including

angioedema

urticaria,

association

with

cinacalcet

administration.

Isolated

idiosyncratic

cases

hypotension and/or

worsening

heart

failure

have

been

reported in

cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance.

Table

shows

adverse

events

from

subjects

with

primary

were

unable

undergo

parathyroidectomy.

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Table 3 Treatment of Hypercalcaemia in Adult Patients with Primary HPT for Whom

Parathyroidectomy Would be Indicated on the Basis of Serum Calcium Levels, but who are Unable to

Undergo Surgery

System Organ Class

Very Common

Common

Gastrointestinal disorders

Nausea

Diarrhea

Musculoskeletal and connective tissue disorders

Muscle spasms

Back pain

Nervous system disorders

Headache

Very common: greater than 10%, common: between 1% and 10%

Table 4 describes adverse reactions identified in the EVOLVE (EValuation Of Cinacalcet HCl Therapy to

Lower CardioVascular Events) clinical trial.

System Organ Class

Very Common

Common

Gastrointestinal disorders

Nausea

Vomiting

Diarrhea

Abdominal pain

Abdominal pain – upper

Constipation

Dyspepsia

Respiratory, thoracic and mediastinal disorders

Dyspnea

Cough

Vascular disorders

Hypotension

Musculoskeletal and connective tissue disorders

Muscle spasms

Metabolism and nutrition disorders

Hyperkalaemia

Infections and infestations

Upper respiratory infection

Nervous system disorders

Headache

Convulsions

Skin and subcutaneous tissue disorders

Rash

Immune system disorders

Hypersensitivity

Very common: greater than 10%, common: between 1% and 10%

c) Description of selected adverse reactions

Laboratory Values

Serum calcium levels should be monitored in patients receiving cinacalcet (see sections 4.4 and 4.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicine is important. It allows continued

monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any

suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/

4.9 Overdose

Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis.

Overdosage of cinacalcet may lead to hypocalcaemia. In the event of overdosage, patients should be

monitored for signs and symptoms of hypocalcaemia and appropriate measures taken to correct serum

calcium levels (see section 4.4).

Since cinacalcet is highly protein bound, hemodialysis is not an effective treatment for overdosage of

cinacalcet.

For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON

(0800 764766).

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5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Anti-Parathyroid Hormones,

ATC code: H05BX01

Cinacalcet is presented in tablets as the hydrochloride salt. Cinacalcet hydrochloride is described chemically

N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane

hydrochloride

following structural formula:

Cinacalcet

calcimimetic

agent

that

increases

sensitivity

calcium

sensing

receptor

extracellular calcium. The empirical formula of cinacalcet hydrochloride is C

NHCl and it has a

molecular weight of 393.9 g/mol (hydrochloride salt) and 357.4 g/mol (free base). It has one chiral centre

having an R-absolute configuration. The R-enantiomer is the more potent enantiomer and has been shown to

be responsible for pharmacodynamic activity.

Cinacalcet hydrochloride is a white to off-white, crystalline solid that is soluble in methanol or 95% ethanol

and poorly soluble in water.

Pharmacodynamic effects

Mechanism of Action

Cinacalcet reduces PTH while simultaneously lowering Ca×P, calcium and phosphorus levels in chronic

kidney disease in patients receiving dialysis.

Secondary hyperparathyroidism (HPT) is a progressive disease, which occurs in patients with chronic kidney

disease (CKD) and manifests as increases in parathyroid hormone (PTH) levels and derangements in calcium

and phosphorus metabolism.

Increased PTH stimulates osteoclastic activity resulting in cortical bone

resorption and marrow fibrosis. The calcium sensing receptor on the surface of the chief cell of the

parathyroid gland is the principal regulator of PTH secretion. Cinacalcet directly lowers PTH levels by

increasing the sensitivity of the calcium sensing receptor to extracellular calcium. The reduction in PTH is

associated with a concomitant decrease in serum calcium levels.

In CKD patients with uncontrolled secondary HPT, reductions in PTH were associated with a favorable

impact on bone specific alkaline phosphatase (BALP), N-telopeptide (N-Tx), bone turnover, bone fibrosis,

and incidence of bone fracture.

Studies in a rat model of chronic renal insufficiency (CRI) (5/6 nephrectomy) assessed the effects of

cinacalcet treatment on parathyroid gland hyperplasia. Cinacalcet treatment reduced PTH and parathyroid

cell proliferation to levels comparable to vehicle-treated, non-nephrectomised animals, demonstrating that

cinacalcet prevented the development of secondary HPT.

Pharmacodynamics

Reductions in PTH levels correlate with cinacalcet concentrations. Nadir PTH occurs approximately 2 to 6

hours

post

dose,

corresponding

with

cinacalcet

After

steady

state

reached,

serum

calcium

concentrations remain constant over the dosing interval.

Clinical efficacy and safety

Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease

Three, 6-month, multicentre, randomized, double-blind, placebo-controlled clinical studies were conducted

in CKD patients receiving dialysis with uncontrolled secondary HPT (n=665 on cinacalcet, 471 on placebo).

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The patient population consisted of both recently established and long-standing dialysis patients, with a

range of 1 to 359 months. Cinacalcet was administered either alone or in combination with vitamin D sterols;

34% of patients were not receiving vitamin D sterols at study entry. The majority (more than 90%) of

patients were receiving phosphate binders. Dose adjustments in phosphate binder therapy were permitted

throughout the study. Vitamin D doses remained constant unless the patient developed hypercalcemia,

hypocalcaemia, or hyperphosphatemia. Patients continued on their previously prescribed drugs including:

calcium

channel

blockers,

inhibitors,

beta-blockers,

hypoglycemics,

lipid

lowering

agents.

Cinacalcet (or placebo) was initiated at a dose of 30 mg and titrated every 3 or 4 weeks to a maximum dose

of 180 mg once daily to achieve an iPTH of 10.6 to 26.5 pmol/L(1.5 to 4 times the upper limit of normal).

The severity of secondary HPT ranged from mild to severe (iPTH values of 28.8 to 969.5 pmol/L), with

mean (SE) baseline iPTH concentrations across the 3 studies of 77.8 (2.2) and 72.5 (2.0) pmol/L for the

cinacalcet and placebo groups, respectively. Significant reductions in iPTH, serum calcium-phosphorus

product (Ca×P), calcium, and phosphorus were observed in the cinacalcet-treated patients compared with

placebo-treated patients receiving standard of care, and the results were consistent across the 3 studies (Table

Table 5. Effects of Cinacalcet on iPTH, Ca×P, Serum Calcium, and Serum Phosphorus in 6-month Phase 3

Studies (Patients Receiving Dialysis)

Study 1

Study 2

Study 3

Placebo

(N = 205)

Cinacalcet

(N = 205)

Placebo

(N = 165)

Cinacalcet

(N = 166)

Placebo

(N = 101)

Cinacalcet

(N = 294)

iPTH

Baseline (pmol/L)

69.1(2.9)

67.5(2.5)

66.8(2.6)

69.2(3.1)

88.3(5.1)

90.0(4.3)

Evaluation Phase (pmol/L)

74.0(3.5)

40.8(2.6)

72.9(3.4)

38.3(3.1)

90.4(5.8)

55.8(3.2)

Percent Change

9.5(2.8)

-38.4(2.9)

8.7(2.8)

-47.5(2.8)

4.1(3.4)

-40.3(2.1)

Patients Achieving Primary

Endpoint

(iPTH ≤26.5 pmol/L) (%)

41%**

46%**

35%**

Patients Achieving ≥30%

Reduction in iPTH (%)

61%**

68%**

59%**

Patients Achieving iPTH

≤31.8 pmol/L (%)

55%**

56%**

45%**

Ca×P

Baseline (mmol

4.93(0.09)

5.00(0.09)

4.92(0.09)

4.92(0.10)

4.91(0.11)

4.80(0.08)

Evaluation Phase (mmol

4.82(0.08)

4.21(0.08)

4.79(0.09)

4.02(0.10)

4.68(0.11)

4.03(0.07)

Percent Change

1.5(1.8)

-13.0(1.7)**

-0.7(1.9)

-16.7(2.1)**

-1.4(2.4)

-12.8(1.7)**

Calcium

Baseline (mmol/L)

2.48(0.01)

2.46(0.01)

2.48(0.01)

2.51(0.01)

2.50(0.02)

2.45(0.01)

Evaluation Phase (mmol/L)

2.48(0.01)

2.30(0.02)

2.48(0.01)

2.31(0.02)

2.52(0.02)

2.28(0.01)

Percent Change

0.5(0.4)

-6.3(0.6)**

0.3(0.4)

-7.5(0.6)**

0.9(0.5)

-6.5(0.6)**

Phosphorus

Baseline (mmol/L)

2.00(0.04)

2.04(0.04)

2.00(0.04)

1.96(0.04)

1.97(0.05)

1.97(0.03)

Evaluation Phase (mmol/L)

1.95(0.03)

1.84(0.04)

1.94(0.04)

1.74(0.04)

1.87(0.04)

1.77(0.03)

Percent Change

1.1(1.8)

-7.1(1.7)**

-0.9(1.9)

-9.9(2.0)**

-2.2(2.5)

-7.2(1.6)*

* p < 0.05; ** p < 0.001 compared to placebo

Data represent mean (standard error) or percent

Mean iPTH and Ca×P by treatment group for the overall

study population during the 6-month treatment period are presented in Figure 1 and Figure 2.

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