Parareg

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 30 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 30 mg cinacalcet (as hydrochloride). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
30 mg: Light green, oval, film-coated tablets marked “AMGEN” on one side and “30” 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.  
 
Parareg may be used as part of a therapeutic regimen including 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 parathyroidectomy is not 
clinically appropriate or is contraindicated. 
 

4.2  Posology and method of administration 
 
For oral use. It is recommended that Parareg be taken with food or shortly after a meal, as studies have 
shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2). Tablets 
should be taken whole and not divided. 
 
Hepatic impairment 
 
No change in starting dose is necessary. Parareg should be used with caution in patients with moderate 
to severe hepatic impairment and treatment should be closely monitored during dose titration and 
continued treatment (see sections 4.4 and 5.2). 
 
Secondary Hyperparathyroidism 
 
Adults and elderly (> 65 years) 
 
The recommended starting dose for adults is 30 mg once per day.  Parareg should be titrated every 2 to 
4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in 
dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH 
levels should be assessed at least 12 hours after dosing with Parareg.  Reference should be made to 
current treatment guidelines.   

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PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Parareg. PTH should be 
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Parareg does not alter the 
relationship between iPTH and biPTH. 
 
Information regarding the pharmacokinetic/pharmacodynamic (PK/PD) profile of cinacalcet is given 
in section 5.1 
 
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of 
initiation or dose adjustment of Parareg. Once the maintenance dose has been established, serum 
calcium should be measured approximately monthly. If serum calcium levels decrease below the 
normal range, appropriate steps should be taken (see section 4.4). Concomitant therapy with phosphate 
binders and/or vitamin D sterols should be adjusted as appropriate. 
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
Adults and elderly (> 65 years) 
 
The recommended starting dose of Parareg for adults is 30 mg twice per day. The dosage of Parareg 
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice 
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium 
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 
90 mg four times daily. 
 
Serum calcium should be measured within 1 week after initiation or dose adjustment of Parareg. Once 
maintenance dose levels have been established, serum calcium should be measured every 2 to 
3 months.  After titration to the maximum dose of Parareg, serum calcium should be periodically 
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of 
Parareg therapy should be considered (see section 5.1).   
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients.  
 
4.4  Special warnings and precautions for use 
 
Seizures 
 
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, five percent of the 
patients in both the Parareg and placebo groups reported a history of seizure disorder at baseline. In 
these studies, seizures were observed in 1.4% of Parareg treated patients and 0.4% 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.   
 

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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. 
 
Serum Calcium 
 
Parareg treatment should not be initiated in patients with a serum calcium (corrected for albumin) 
below the lower limit of the normal range. Since cinacalcet lowers serum calcium, patients should be 
monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving 
dialysis who were administered Parareg, 4% of serum calcium values were less than 7.5 mg/dl 
(1.875 mmol/l).   In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D 
sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. 
If hypocalcaemia persists, reduce the dose or discontinue administration of Parareg..  Potential 
manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and 
convulsions.  
 
Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that 
CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum 
calcium levels < 8.4 mg/dl [2.1 mmol/l]) compared with cinacalcet-treated CKD patients on dialysis, 
which may be due to lower baseline calcium levels and/or the presence of residual kidney function. 
 
General  
 
Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 
1.5 times the upper limit of normal with the iPTH assay.  If PTH levels decrease below the 
recommended target range in patients treated with Parareg, the dose of Parareg and/or vitamin D 
sterols should be reduced or therapy discontinued. 
 
Testosterone Levels 
 
Testosterone levels are often below the normal range in patients with end-stage renal disease.  In a 
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in 
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.  
An open-label extension of this study showed no further reductions in free and total testosterone 
concentrations over a period of 3 years in Mimpara-treated patients.  The clinical significance of these 
reductions in serum testosterone is unknown. 
 
Hepatic Insufficiency 
 
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to 
severe hepatic impairment (Child-Pugh classification), Parareg should be used with caution in these 
patients and treatment should be closely monitored (see sections 4.2 and 5.2). 
 
Interactions 
 
Caution should be exercised when administering Parareg concomitantly with strong inhibitors or 
inducers of CYP3A4 and/or CYP1A2. Dose adjustment of Parareg may be necessary (see section 4.5). 
 
Caution should be exercised when Parareg is administered with individually titrated, narrow 
therapeutic index medications that are predominantly metabolised by CYP2D6. Dose adjustments of 
concomitant medications may be necessary (see section 4.5). 
 

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Plasma levels of cinacalcet may be lower in smokers due to induction of CYP1A2-mediated 
metabolism. Dose adjustments may be necessary if a patient starts or stops smoking during cinacalcet 
treatment (see section 4.5). 
 
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 mg bid 
ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet 
levels.  Dose adjustment of Parareg may be required if a patient receiving Parareg initiates or 
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, 
voriconazole, ritonavir) or inducer (eg rifampicin) of this enzyme (see Section 4.4). 
 
In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induces CYP1A2; 
the clearance of cinacalcet was observed to be 36-38% higher in smokers than non-smokers. The 
effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not 
been studied. Dose adjustment may be necessary if a patient starts or stops smoking or when 
concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.  
 
Calcium carbonate:  Co-administration of calcium carbonate (single 1500 mg dose) did not alter the 
pharmacokinetics of cinacalcet. 
 
Sevelamer:  Co-administration of sevelamer (2400 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 medications 
 
Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor 
of CYP2D6.  Dose adjustments of concomitant medicinal products may be required when Parareg is 
administered with individually titrated, narrow therapeutic index substances that are predominantly 
metabolised by CYP2D6 (e.g., flecainide, propafenone, metoprolol given in heart failure, desipramine, 
nortriptyline, clomipramine) (see section 4.4).   
 
Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a 
tricyclic antidepressant metabolised primarily by CYP2D6, significantly increased desipramine 
exposure 3.6-fold (90 % CI 3.0, 4.4) in CYP2D6 extensive metabolisers. 
 
Warfarin:  Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics 
(as measured by prothrombin time and clotting factor VII) of warfarin.   
 
The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-
induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP3A4, 
CYP1A2 or CYP2C9 in humans. 
 
Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a 
CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam.  These data 
suggest that cinacalcet would not affect the pharmacokinetics of those classes of drugs that are 
metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine 
and tacrolimus. 
 

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4.6 Pregnancy and lactation 
 
There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not 
indicate direct harmful effects with respect to pregnancy, parturition or postnatal development.  No 
embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of 
decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3).  
Parareg should be used during pregnancy only if the potential benefit justifies the potential risk to the 
foetus. 
 
It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of 
lactating rats with a high milk to plasma ratio. Following careful benefit/risk assessment, a decision 
should be made to discontinue either breast-feeding or treatment with Parareg. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
 
4.8    Undesirable effects 
 
Secondary Hyperparathyroidism 
 
Data presented from controlled studies include 656 patients who received Parareg and 470 patients 
who received placebo for up to 6 months. The most commonly reported undesirable effects were 
nausea and vomiting, occurring in 31% Parareg and 19% placebo treated patients, and 27% Parareg 
and 15% placebo treated patients, respectively.  Nausea and vomiting were mild to moderate in 
severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of 
undesirable effects was mainly due to nausea (1% placebo; 5% cinacalcet) and vomiting (< 1% 
placebo; 4% cinacalcet).  
 
Adverse reactions, defined as adverse events considered at least possibly attributable to cinacalcet 
treatment based on best-evidence assessment of causality and reported in excess of placebo in double-
blind clinical studies are listed below using the following convention: very common (> 1/10); common 
(> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare 
(< 1/10,000). 
 
Immune system disorders 
Uncommon: hypersensitivity reactions 
 
Metabolism and nutrition disorders 
Common:  anorexia 
 
Nervous system disorders 
Common:  dizziness, paraesthesia 
Uncommon:  seizures  
 
Gastrointestinal disorders 
Very common: nausea, vomiting  
Uncommon:  dyspepsia, diarrhoea 
 
Skin and subcutaneous tissue disorders 
Common:  rash 
 
Musculoskeletal, connective tissue and bone disorders 
Common:  myalgia 
 
General disorders and administration site conditions 
Common:  asthenia 

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Investigations 
Common:  hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4) 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
The safety profile of Parareg in these patient populations is generally consistent with that seen in 
patients with Chronic Kidney Disease. The most frequent ADRs in these patient populations were 
nausea and vomiting.  
 
Post-marketing Experience 
 
There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart failure 
in cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance. 
 
4.9 Overdose 
 
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis. 
 
Overdosage of Parareg may lead to hypocalcaemia. In the event of overdosage, patients should be 
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and 
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for 
overdosage. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: 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 secretion. Cinacalcet is a calcimimetic agent which 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. 
 
Reductions in PTH levels correlate with cinacalcet concentration.  Soon after dosing, PTH begins to 
decrease until a nadir at approximately 2 to 6 hours postdose, corresponding with cinacalcet Cmax.  
Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and 
then PTH suppression remains approximately constant to the end of the once-daily dosing interval. 
PTH levels in Parareg clinical trials were measured at the end of the dosing interval. 
 
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 patients 
with uncontrolled secondary HPT receiving dialysis (n=1136). Demographic and baseline 
characteristics were representative of the dialysis patient population with secondary HPT. Mean 
baseline iPTH concentrations across the 3 studies were 733 and 683 pg/ml (77.8 and 72.4 pmol/l) for 
the cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols at 
study entry, and > 90% were receiving phosphate binders.  Significant reductions in iPTH, serum 
calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet treated 
patients compared with placebo-treated patients receiving standard of care, and the results were 

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consistent across the 3 studies.  In each of the studies, the primary endpoint (proportion of patients 
with an iPTH ≤ 250 pg/ml (≤ 26.5 pmol/l)) was achieved by 41%, 46%, and 35% of patients receiving 
cinacalcet, compared with 4%, 7%, and 6% of patients receiving placebo.  Approximately 60% of 
cinacalcet-treated patients achieved a ≥ 30% reduction in iPTH levels, and this effect was consistent 
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.  Cinacalcet 
decreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x P 
level, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols 
were administered.   
 
Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bone 
specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses of 
pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture and 
parathyroidectomy were lower in the cinacalcet group compared with the control group. 
 
Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated that 
cinacalcet reduced PTH levels to a similar extent as in patients with ESRD and secondary HPT 
receiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not been 
established in treatment of predialytic renal failure patients. These studies show that CKD patients not 
undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with 
cinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calcium 
levels. 
 
Parathyroid carcinoma and Primary Hyperparathyroidism 
 
In a key study,46 patients (29 with parathyroid carcinoma and 17 with primary HPT (who had failed 
or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean of 328 days 
for patients with parathyroid carcinoma and mean of 347 days for patients 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 mg/dl (≥ 0.25 mmol/l). In 
patients with parathyroid carcinoma, mean serum calcium declined from  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 of 29 patients (62 %) with parathyroid 
carcinoma and 15 of 17 subjects (88 %) with primary HPT achieved a reduction in serum calcium of ≥ 
1 mg/dl (≥ 0.25 mmol/l).  
 
5.2 Pharmacokinetic properties 
 
After oral administration of Parareg, maximum plasma cinacalcet concentration is achieved in 
approximately 2 to 6 hours.   
 
Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has 
been estimated to be about 20-25%.  Administration of Parareg with food results in an approximate 50 
– 80% increase in cinacalcet bioavailability.  Increases in plasma cinacalcet concentration are similar, 
regardless of the fat content of the meal. 
 
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of 
approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved 
within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase approximately 
linearly over the dose range of 30 to 180 mg once daily. At doses above 200 mg, the absorption was 
saturated probably due to poor solubility.  The pharmacokinetics of cinacalcet does not change over 
time.  The volume of distribution is high (approximately 1000 litres), indicating extensive distribution.  
Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood 
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Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the 
contribution of CYP1A2 has not been characterised clinically).  The major circulating metabolites are 
inactive. 
 
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 and 
extensively metabolised by oxidation followed by conjugation.  Renal excretion of metabolites was 
the prevalent route of elimination of radioactivity.  Approximately 80% of the dose was recovered in 
the urine and 15% in the faeces. 
 
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 impairment did not notably affect the pharmacokinetics of 
cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was 
approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in 
subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in 
patients with moderate and severe hepatic impairment, respectively.  Protein binding of cinacalcet is 
not affected by impaired hepatic function. Because doses are titrated for each subject based on safety 
and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic 
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. 
 
Children and adolescents:  The pharmacokinetics of cinacalcet have not been studied in patients < 18 
years of age. 
 
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 may 
change and dose adjustment may 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 
maximum human dose for secondary HPT (180 mg daily).  The non-teratogenic dose in rats was 4.4 
times, on an AUC basis, the maximum dose for secondary HPT.  There were no effects on fertility in 
males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small 
population of patients administered a maximum clinical dose of 360 mg daily would be approximately 
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.  Cinacalcet 
has been shown to cross the placental barrier in rabbits. 
 
Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology 
studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and 
lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were 

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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 serotonin transporter and KATP channels were found to be 7 and 
12 fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same 
experimental conditions.  The clinical relevance 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 
 
Pre-gelatinised starch (maize) 
Microcrystalline cellulose 
Povidone 
Crospovidone 
Magnesium stearate 
Colloidal anhydrous silica 
 
Tablet Coat 
 
Carnauba Wax 
Opadry II green:  (Lactose monohydrate, hypromellose, titanium dioxide (E171), 

glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172) 
Opadry clear:   (Hypromellose, macrogol) 
Opacode Black, printing ink: (Shellac glaze (shellac), iron oxide black (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Blister:  4 years. 
Bottle:  4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aclar/PVC/PVAc/Aluminium blister containing 14 tablets. Pack sizes of 1 blister (14 tablets), 2 
blisters (28 tablets), 6 blisters (84 tablets) per carton. 
 
High Density Polyethylene (HDPE) bottle with a desiccant canister and polyester coil, and a child-
resistant polypropylene cap with an induction seal, packed into a carton. Each bottle contains 30 
tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 

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7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/001-003 
EU/1/04/293/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
22 October 2004 
 
 
10. DATE OF REVISION OF THE TEXT 

 
  

 
 

Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/

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http://www.emea.europa.eu/


 

1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 60 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 60 mg cinacalcet  (as hydrochloride). 
 
For a full list of  excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
60 mg: Light green, oval, film-coated tablets marked “AMGEN” on one side and “60” 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.  
 
Parareg may be used as part of a therapeutic regimen including 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 parathyroidectomy is not 
clinically appropriate or is contraindicated. 
 

4.2  Posology and method of administration 
 
For oral use. It is recommended that Parareg be taken with food or shortly after a meal, as studies have 
shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2). Tablets 
should be taken whole and not divided. 
 
Hepatic impairment 
 
No change in starting dose is necessary. Parareg should be used with caution in patients with moderate 
to severe hepatic impairment and treatment should be closely monitored during dose titration and 
continued treatment (see sections 4.4 and 5.2). 
 
Secondary Hyperparathyroidism 
 
Adults and elderly (> 65 years) 
 
The recommended starting dose for adults is 30 mg once per day.  Parareg should be titrated every 2 to 
4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in 
dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH 
levels should be assessed at least 12 hours after dosing with Parareg.  Reference should be made to 
current treatment guidelines.   

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PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Parareg. PTH should be 
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Parareg does not alter the 
relationship between iPTH and biPTH. 
 
Information regarding the pharmacokinetic/pharmacodynamic (PK/PD) profile of cinacalcet is given 
in section 5.1 
 
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of 
initiation or dose adjustment of Parareg. Once the maintenance dose has been established, serum 
calcium should be measured approximately monthly. If serum calcium levels decrease below the 
normal range, appropriate steps should be taken (see section 4.4). Concomitant therapy with phosphate 
binders and/or vitamin D sterols should be adjusted as appropriate. 
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
Adults and elderly (>65 years) 
 
The recommended starting dose of Parareg for adults is 30 mg twice per day. The dosage of Parareg 
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice 
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium 
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 
90 mg four times daily. 
 
Serum calcium should be measured within 1 week after initiation or dose adjustment of Parareg. Once 
maintenance dose levels have been established, serum calcium should be measured every 2 to 
3 months.  After titration to the maximum dose of Parareg, serum calcium should be periodically 
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of 
Parareg therapy should be considered (see section 5.1).   
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients.  
 
4.4  Special warnings and precautions for use 
 
Seizures 
 
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, five percent of the 
patients in both the Parareg and placebo groups reported a history of seizure disorder at baseline. In 
these studies, seizures were observed in 1.4% of Parareg treated patients and 0.4% 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.   
 

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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. 
 
Serum Calcium 
 
Parareg treatment should not be initiated in patients with a serum calcium (corrected for albumin) 
below the lower limit of the normal range. Since cinacalcet lowers serum calcium, patients should be 
monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving 
dialysis who were administered Parareg, 4% of serum calcium values were less than 7.5 mg/dl 
(1.875 mmol/l).   In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D 
sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. 
If hypocalcaemia persists, reduce the dose or discontinue administration of Parareg.  Potential 
manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and 
convulsions.  
 
Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that 
CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum 
calcium levels < 8.4 mg/dl [2.1 mmol/l]) compared with cinacalcet-treated CKD patients on dialysis, 
which may be due to lower baseline calcium levels and/or the presence of residual kidney function. 
 
General  
 
Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 
1.5 times the upper limit of normal with the iPTH assay.  If PTH levels decrease below the 
recommended target range in patients treated with Parareg, the dose of Parareg and/or vitamin D 
sterols should be reduced or therapy discontinued. 
 
Testosterone Levels 
 
Testosterone levels are often below the normal range in patients with end-stage renal disease.  In a 
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in 
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.  
An open-label extension of this study showed no further reductions in free and total testosterone 
concentrations over a period of 3 years in Mimpara-treated patients.  The clinical significance of these 
reductions in serum testosterone is unknown. 
 
Hepatic Insufficiency 
 
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to 
severe hepatic impairment (Child-Pugh classification), Parareg should be used with caution in these 
patients and treatment should be closely monitored (see sections 4.2 and 5.2). 
 
Interactions 
 
Caution should be exercised when administering Parareg concomitantly with strong inhibitors or 
inducers of CYP3A4 and/or CYP1A2. Dose adjustment of Parareg may be necessary (see section 4.5). 
 
Caution should be exercised when Parareg is administered with individually titrated, narrow 
therapeutic index medications that are predominantly metabolised by CYP2D6. Dose adjustments of 
concomitant medications may be necessary (see section 4.5). 
 

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Plasma levels of cinacalcet may be lower in smokers due to induction of CYP1A2-mediated 
metabolism. Dose adjustments may be necessary if a patient starts or stops smoking during cinacalcet 
treatment (see section 4.5). 
 
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 mg bid 
ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet 
levels.  Dose adjustment of Parareg may be required if a patient receiving Parareg initiates or 
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, 
voriconazole, ritonavir) or inducer (eg rifampicin) of this enzyme (see Section 4.4). 
 
In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induces CYP1A2; 
the clearance of cinacalcet was observed to be 36-38% higher in smokers than non-smokers. The 
effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not 
been studied. Dose adjustment may be necessary if a patient starts or stops smoking or when 
concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.  
 
Calcium carbonate:  Co-administration of calcium carbonate (single 1500 mg dose) did not alter the 
pharmacokinetics of cinacalcet. 
 
Sevelamer:  Co-administration of sevelamer (2400 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 medications 
 
Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor 
of CYP2D6.  Dose adjustments of concomitant medicinal products may be required when Parareg is 
administered with individually titrated, narrow therapeutic index substances that are predominantly 
metabolised by CYP2D6 (e.g., flecainide, propafenone, metoprolol given in heart failure, 
desimipramine, nortriptyline, clomipramine) (see section 4.4).   
 
Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a 
tricyclic antidepressant metabolised primarily by CYP2D6, significantly increased desipramine 
exposure 3.6-fold (90 % CI 3.0, 4.4) in CYP2D6 extensive metabolisers. 
 
Warfarin:  Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics 
(as measured by prothrombin time and clotting factor VII) of warfarin.   
 
The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-
induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP3A4, 
CYP1A2 or CYP2C9 in humans. 
 
Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a 
CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam.  These data 
suggest that cinacalcet would not affect the pharmacokinetics of those classes of drugs that are 
metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine 
and tacrolimus. 
 

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4.6 Pregnancy and lactation 
 
There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not 
indicate direct harmful effects with respect to pregnancy, parturition or postnatal development.  No 
embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of 
decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3).  
Parareg should be used during pregnancy only if the potential benefit justifies the potential risk to the 
foetus. 
 
It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of 
lactating rats with a high milk to plasma ratio. Following careful benefit/risk assessment, a decision 
should be made to discontinue either breast-feeding or treatment with Parareg. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
 
4.8    Undesirable effects 
 
Secondary Hyperparathyroidism 
 
Data presented from controlled studies include 656 patients who received Parareg and 470 patients 
who received placebo for up to 6 months. The most commonly reported undesirable effects were 
nausea and vomiting, occurring in 31% Parareg and 19% placebo treated patients, and 27% Parareg 
and 15% placebo treated patients, respectively.  Nausea and vomiting were mild to moderate in 
severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of 
undesirable effects was mainly due to nausea (1% placebo; 5% cinacalcet) and vomiting (< 1% 
placebo; 4% cinacalcet).  
 
Adverse reactions, defined as adverse events considered at least possibly attributable to cinacalcet 
treatment based on best-evidence assessment of causality and reported in excess of placebo in double-
blind clinical studies are listed below using the following convention: very common (> 1/10); common 
(> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare 
(< 1/10,000). 
 
Immune system disorders 
Uncommon: hypersensitivity reactions 
 
Metabolism and nutrition disorders 
Common:  anorexia 
 
Nervous system disorders 
Common:  dizziness, paraesthesia 
Uncommon:  seizures  
 
Gastrointestinal disorders 
Very common: nausea, vomiting  
Uncommon:  dyspepsia, diarrhoea 
 
Skin and subcutaneous tissue disorders 
Common:  rash 
 
Musculoskeletal, connective tissue and bone disorders 
Common:  myalgia 
 
General disorders and administration site conditions 
Common:  asthenia 

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Investigations 
Common:  hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4) 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
The safety profile of Parareg in these patient populations is generally consistent with that seen in 
patients with Chronic Kidney Disease. The most frequent ADRs in these patient populations were 
nausea and vomiting.  
 
Post-marketing Experience 
 
There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart failure 
in cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance. 
 
4.9 Overdose 
 
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis. 
 
Overdosage of Parareg may lead to hypocalcaemia. In the event of overdosage, patients should be 
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and 
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for 
overdosage. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: 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 secretion. Cinacalcet is a calcimimetic agent which 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. 
 
Reductions in PTH levels correlate with cinacalcet concentration.  Soon after dosing, PTH begins to 
decrease until a nadir at approximately 2 to 6 hours postdose, corresponding with cinacalcet Cmax.  
Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and 
then PTH suppression remains approximately constant to the end of the once-daily dosing interval. 
PTH levels in Parareg clinical trials were measured at the end of the dosing interval. 
 
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 patients 
with uncontrolled secondary HPT receiving dialysis (n=1136). Demographic and baseline 
characteristics were representative of the dialysis patient population with secondary HPT. Mean 
baseline iPTH concentrations across the 3 studies were 733 and 683 pg/ml (77.8 and 72.4 pmol/l) for 
the cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols at 
study entry, and > 90% were receiving phosphate binders.  Significant reductions in iPTH, serum 
calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet treated 
patients compared with placebo-treated patients receiving standard of care, and the results were 

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consistent across the 3 studies.  In each of the studies, the primary endpoint (proportion of patients 
with an iPTH ≤ 250 pg/ml (≤ 26.5 pmol/l)) was achieved by 41%, 46%, and 35% of patients receiving 
cinacalcet, compared with 4%, 7%, and 6% of patients receiving placebo.  Approximately 60% of 
cinacalcet-treated patients achieved a ≥ 30% reduction in iPTH levels, and this effect was consistent 
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.  Cinacalcet 
decreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x P 
level, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols 
were administered.   
 
Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bone 
specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses of 
pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture and 
parathyroidectomy were lower in the cinacalcet group compared with the control group. 
 
Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated that 
cinacalcet reduced PTH levels to a similar extent as in patients with ESRD and secondary HPT 
receiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not been 
established in treatment of predialytic renal failure patients. These studies show that CKD patients not 
undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with 
cinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calcium 
levels and/or the presence of residual kidney function. 
 
Parathyroid carcinoma and Primary Hyperparathyroidism 
 
In a key study,46 patients (29 with parathyroid carcinoma and 17 with primary HPT (who had failed 
or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean of 328 days 
for patients with parathyroid carcinoma and mean of 347 days for patients 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 mg/dl (≥ 0.25 mmol/l). In 
patients with parathyroid carcinoma, mean serum calcium declined from  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 of 29 patients (62 %) with parathyroid 
carcinoma and 15 of 17 subjects (88 %) with primary HPT achieved a reduction in serum calcium of ≥ 
1 mg/dl (≥ 0.25 mmol/l).  
 
5.2   Pharmacokinetic properties 
 
After oral administration of Parareg, maximum plasma cinacalcet concentration is achieved in 
approximately 2 to 6 hours.   
 
Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has 
been estimated to be about 20-25%.  Administration of Parareg with food results in an approximate 50 
– 80% increase in cinacalcet bioavailability.  Increases in plasma cinacalcet concentration are similar, 
regardless of the fat content of the meal. 
 
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of 
approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved 
within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase approximately 
linearly over the dose range of 30 to 180 mg once daily. At doses above 200 mg, the absorption was 
saturated probably due to poor solubility.  The pharmacokinetics of cinacalcet does not change over 
time.  The volume of distribution is high (approximately 1000 litres), indicating extensive distribution.  
Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood 
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Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the 
contribution of CYP1A2 has not been characterised clinically).  The major circulating metabolites are 
inactive. 
 
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 and 
extensively metabolised by oxidation followed by conjugation.  Renal excretion of metabolites was 
the prevalent route of elimination of radioactivity.  Approximately 80% of the dose was recovered in 
the urine and 15% in the faeces. 
 
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 impairment did not notably affect the pharmacokinetics of 
cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was 
approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in 
subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in 
patients with moderate and severe hepatic impairment, respectively.  Protein binding of cinacalcet is 
not affected by impaired hepatic function. Because doses are titrated for each subject based on safety 
and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic 
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. 
 
Children and adolescents:  The pharmacokinetics of cinacalcet have not been studied in patients < 18 
years of age. 
 
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 may 
change and dose adjustment may 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 
maximum human dose for secondary HPT (180 mg daily).  The non-teratogenic dose in rats was 4.4 
times, on an AUC basis, the maximum dose for secondary HPT.  There were no effects on fertility in 
males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small 
population of patients administered a maximum clinical dose of 360 mg daily would be approximately 
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.  Cinacalcet 
has been shown to cross the placental barrier in rabbits. 
 
Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology 
studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and 
lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were 

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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 serotonin transporter and KATP channels were found to be 7 and 
12 fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same 
experimental conditions.  The clinical relevance 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 
 
Pre-gelatinised starch (maize) 
Microcrystalline cellulose 
Povidone 
Crospovidone 
Magnesium stearate 
Colloidal anhydrous silica 
 
Tablet Coat 
 
Carnauba Wax 
Opadry II green:  (Lactose monohydrate, hypromellose, titanium dioxide (E171), 

glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172) 
Opadry clear:   (Hypromellose, macrogol) 
Opacode Black, printing ink: (Shellac glaze (shellac), iron oxide black (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Blister:  4 years. 
Bottle:  4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aclar/PVC/PVAc/Aluminium blister containing 14 tablets. Pack sizes of 1 blister (14 tablets), 2 
blisters (28 tablets), 6 blisters (84 tablets) per carton. 
 
High Density Polyethylene (HDPE) bottle with a desiccant canister and polyester coil, and a child-
resistant polypropylene cap with an induction seal, packed into a carton. Each bottle contains 30 
tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 

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7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/005-007 
EU/1/04/293/008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
22 October 2004 
 
 
10. DATE OF REVISION OF THE TEXT 
 
  
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/

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http://www.emea.europa.eu/


 

1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 90 mg film-coated tablets. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 90 mg cinacalcet (as hydrochloride). 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
90 mg: Light green, oval, film-coated tablets marked “AMGEN” on one side and “90” 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.  
 
Parareg may be used as part of a therapeutic regimen including 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 parathyroidectomy is not 
clinically appropriate or is contraindicated. 
 

4.2  Posology and method of administration 
 
For oral use. It is recommended that Parareg be taken with food or shortly after a meal, as studies have 
shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2). Tablets 
should be taken whole and not divided. 
 
Hepatic impairment 
 
No change in starting dose is necessary. Parareg should be used with caution in patients with moderate 
to severe hepatic impairment and treatment should be closely monitored during dose titration and 
continued treatment (see sections 4.4 and 5.2). 
 
Secondary Hyperparathyroidism 
 
Adults and elderly (> 65 years) 
 
The recommended starting dose for adults is 30 mg once per day.  Parareg should be titrated every 2 to 
4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in 
dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH 
levels should be assessed at least 12 hours after dosing with Parareg.  Reference should be made to 
current treatment guidelines.   

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PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Parareg. PTH should be 
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Parareg does not alter the 
relationship between iPTH and biPTH. 
 
Information regarding the pharmacokinetic/pharmacodynamic (PK/PD) profile of cinacalcet is given 
in section 5.1 
 
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of 
initiation or dose adjustment of Parareg. Once the maintenance dose has been established, serum 
calcium should be measured approximately monthly. If serum calcium levels decrease below the 
normal range, appropriate steps should be taken (see section 4.4). Concomitant therapy with phosphate 
binders and/or vitamin D sterols should be adjusted as appropriate. 
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
Adults and elderly (>65 years) 
 
The recommended starting dose of Parareg for adults is 30 mg twice per day. The dosage of Parareg 
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice 
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium 
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 
90 mg four times daily. 
 
Serum calcium should be measured within 1 week after initiation or dose adjustment of Parareg. Once 
maintenance dose levels have been established, serum calcium should be measured every 2 to 3 
months.  After titration to the maximum dose of Parareg, serum calcium should be periodically 
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of 
Parareg therapy should be considered (see section 5.1).   
 
Children and adolescents 
 
Safety and efficacy have not been established in patients below the age of 18 years. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients.  
 
4.4  Special warnings and precautions for use 
 
Seizures 
 
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, five percent of the 
patients in both the Parareg and placebo groups reported a history of seizure disorder at baseline. In 
these studies, seizures were observed in 1.4% of Parareg treated patients and 0.4% 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.   
 

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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. 
 
Serum Calcium 
 
Parareg treatment should not be initiated in patients with a serum calcium (corrected for albumin) 
below the lower limit of the normal range. Since cinacalcet lowers serum calcium, patients should be 
monitored carefully for the occurrence of hypocalcaemia (see section 4.2). In CKD patients receiving 
dialysis who were administered Parareg, 4% of serum calcium values were less than 7.5 mg/dl 
(1.875 mmol/l).   In the event of hypocalcaemia, calcium-containing phosphate binders, vitamin D 
sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium. 
If hypocalcaemia persists, reduce the dose or discontinue administration of Parareg..  Potential 
manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and 
convulsions.  
 
Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that 
CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum 
calcium levels < 8.4 mg/dl [2.1 mmol/l]) compared with cinacalcet-treated CKD patients on dialysis, 
which may be due to lower baseline calcium levels and/or the presence of residual kidney function. 
 
General  
 
Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 
1.5 times the upper limit of normal with the iPTH assay.  If PTH levels decrease below the 
recommended target range in patients treated with Parareg, the dose of Parareg and/or vitamin D 
sterols should be reduced or therapy discontinued. 
 
Testosterone Levels 
 
Testosterone levels are often below the normal range in patients with end-stage renal disease.  In a 
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in 
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.  
An open-label extension of this study showed no further reductions in free and total testosterone 
concentrations over a period of 3 years in Mimpara-treated patients.  The clinical significance of these 
reductions in serum testosterone is unknown. 
 
Hepatic Insufficiency 
 
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to 
severe hepatic impairment (Child-Pugh classification), Parareg should be used with caution in these 
patients and treatment should be closely monitored (see sections 4.2 and 5.2). 
 
Interactions 
 
Caution should be exercised when administering Parareg concomitantly with strong inhibitors or 
inducers of CYP3A4 and/or CYP1A2. Dose adjustment of Parareg may be necessary (see section 4.5). 
 
Caution should be exercised when Parareg is administered with individually titrated, narrow 
therapeutic index medications that are predominantly metabolised by CYP2D6. Dose adjustments of 
concomitant medications may be necessary (see section 4.5). 
 

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Plasma levels of cinacalcet may be lower in smokers due to induction of CYP1A2-mediated 
metabolism. Dose adjustments may be necessary if a patient starts or stops smoking during cinacalcet 
treatment (see section 4.5). 
 
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 mg bid 
ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet 
levels.  Dose adjustment of Parareg may be required if a patient receiving Parareg initiates or 
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, 
voriconazole, ritonavir) or inducer (eg rifampicin) of this enzyme (see Section 4.4). 
 
In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induces CYP1A2; 
the clearance of cinacalcet was observed to be 36-38% higher in smokers than non-smokers. The 
effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not 
been studied. Dose adjustment may be necessary if a patient starts or stops smoking or when 
concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.  
 
Calcium carbonate:  Co-administration of calcium carbonate (single 1500 mg dose) did not alter the 
pharmacokinetics of cinacalcet. 
 
Sevelamer:  Co-administration of sevelamer (2400 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 medications 
 
Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor 
of CYP2D6.  Dose adjustments of concomitant medicinal products may be required when Parareg is 
administered with individually titrated, narrow therapeutic index substances that are predominantly 
metabolised by CYP2D6 (e.g., flecainide, propafenone, metoprolol given in heart failure, 
desimipramine, nortriptyline, clomipramine) (see section 4.4).   
 
Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a 
tricyclic antidepressant metabolised primarily by CYP2D6, significantly increased desipramine 
exposure 3.6-fold (90 % CI 3.0, 4.4) in CYP2D6 extensive metabolizers. 
 
Warfarin:  Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics 
(as measured by prothrombin time and clotting factor VII) of warfarin.   
 
The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-
induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP3A4, 
CYP1A2 or CYP2C9 in humans. 
 
Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a 
CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam.  These data 
suggest that cinacalcet would not affect the pharmacokinetics of those classes of drugs that are 
metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine 
and tacrolimus. 
 

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4.6 Pregnancy and lactation 
 
There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not 
indicate direct harmful effects with respect to pregnancy, parturition or postnatal development.  No 
embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of 
decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3).  
Parareg should be used during pregnancy only if the potential benefit justifies the potential risk to the 
foetus. 
 
It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of 
lactating rats with a high milk to plasma ratio. Following careful benefit/risk assessment, a decision 
should be made to discontinue either breast-feeding or treatment with Parareg. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effects on the ability to drive and use machines have been performed. 
 
4.8    Undesirable effects 
 
Secondary Hyperparathyroidism 
 
Data presented from controlled studies include 656 patients who received Parareg and 470 patients 
who received placebo for up to 6 months. The most commonly reported undesirable effects were 
nausea and vomiting, occurring in 31% Parareg and 19% placebo treated patients, and 27% Parareg 
and 15% placebo treated patients, respectively.  Nausea and vomiting were mild to moderate in 
severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of 
undesirable effects was mainly due to nausea (1% placebo; 5% cinacalcet) and vomiting (< 1% 
placebo; 4% cinacalcet).  
 
Adverse reactions, defined as adverse events considered at least possibly attributable to cinacalcet 
treatment based on best-evidence assessment of causality and reported in excess of placebo in double-
blind clinical studies are listed below using the following convention: very common (> 1/10); common 
(> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare 
(< 1/10,000). 
 
Immune system disorders 
Uncommon: hypersensitivity reactions 
 
Metabolism and nutrition disorders 
Common:  anorexia 
 
Nervous system disorders 
Common:  dizziness, paraesthesia 
Uncommon:  seizures  
 
Gastrointestinal disorders 
Very common: nausea, vomiting  
Uncommon:  dyspepsia, diarrhoea 
 
Skin and subcutaneous tissue disorders 
Common:  rash 
 
Musculoskeletal, connective tissue and bone disorders 
Common:  myalgia 
 
General disorders and administration site conditions 
Common:  asthenia 

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Investigations 
Common:  hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4) 
 
Parathyroid Carcinoma and Primary Hyperparathyroidism 
 
The safety profile of Parareg in these patient populations is generally consistent with that seen in 
patients with Chronic Kidney Disease. The most frequent ADRs in these patient populations were 
nausea and vomiting.  
 
Post-marketing Experience 
 
There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart failure 
in cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance. 
 
4.9 Overdose 
 
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis. 
 
Overdosage of Parareg may lead to hypocalcaemia. In the event of overdosage, patients should be 
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and 
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for 
overdosage. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: 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 secretion. Cinacalcet is a calcimimetic agent which 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. 
 
Reductions in PTH levels correlate with cinacalcet concentration.  Soon after dosing, PTH begins to 
decrease until a nadir at approximately 2 to 6 hours postdose, corresponding with cinacalcet Cmax.  
Thereafter, as cinacalcet levels begin to decline, PTH levels increase until 12 hours post-dose, and 
then PTH suppression remains approximately constant to the end of the once-daily dosing interval. 
PTH levels in Parareg clinical trials were measured at the end of the dosing interval. 
 
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 patients 
with uncontrolled secondary HPT receiving dialysis (n=1136). Demographic and baseline 
characteristics were representative of the dialysis patient population with secondary HPT. Mean 
baseline iPTH concentrations across the 3 studies were 733 and 683 pg/ml (77.8 and 72.4 pmol/l) for 
the cinacalcet and placebo groups, respectively. 66% of patients were receiving vitamin D sterols at 
study entry, and > 90% were receiving phosphate binders.  Significant reductions in iPTH, serum 
calcium-phosphorus product (Ca x P), calcium, and phosphorus were observed in the cinacalcet treated 
patients compared with placebo-treated patients receiving standard of care, and the results were 

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consistent across the 3 studies.  In each of the studies, the primary endpoint (proportion of patients 
with an iPTH ≤ 250 pg/ml (≤ 26.5 pmol/l)) was achieved by 41%, 46%, and 35% of patients receiving 
cinacalcet, compared with 4%, 7%, and 6% of patients receiving placebo.  Approximately 60% of 
cinacalcet-treated patients achieved a ≥ 30% reduction in iPTH levels, and this effect was consistent 
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.  Cinacalcet 
decreased iPTH and Ca x P, calcium and phosphorus levels regardless of baseline iPTH or Ca x P 
level, dialysis modality (PD versus HD), duration of dialysis, and whether or not vitamin D sterols 
were administered.   
 
Reductions in PTH were associated with non-significant reductions of bone metabolism markers (bone 
specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc analyses of 
pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone fracture and 
parathyroidectomy were lower in the cinacalcet group compared with the control group. 
 
Investigational studies in patients with CKD and secondary HPT not undergoing dialysis indicated that 
cinacalcet reduced PTH levels to a similar extent as in patients with ESRD and secondary HPT 
receiving dialysis. However, efficacy, safety, optimal doses and treatment targets have not been 
established in treatment of predialytic renal failure patients. These studies show that CKD patients not 
undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with 
cinacalcet-treated ESRD patients receiving dialysis, which may be due to lower baseline calcium 
levels and/or the presence of residual kidney function. 
 
Parathyroid carcinoma and Primary Hyperparathyroidism 
 
In a key study,46 patients (29 with parathyroid carcinoma and 17 with primary HPT (who had failed 
or had contraindications to parathyroidectomy) received cinacalcet for up to 3 years (mean of 328 days 
for patients with parathyroid carcinoma and mean of 347 days for patients 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 mg/dl (≥ 0.25 mmol/l). In 
patients with parathyroid carcinoma, mean serum calcium declined from  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 of 29 patients (62 %) with parathyroid 
carcinoma and 15 of 17 subjects (88 %) with primary HPT achieved a reduction in serum calcium of ≥ 
1 mg/dl (≥ 0.25 mmol/l).  
 
5.2  Pharmacokinetic properties 
 
After oral administration of Parareg, maximum plasma cinacalcet concentration is achieved in 
approximately 2 to 6 hours.   
 
Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has 
been estimated to be about 20-25%.  Administration of Parareg with food results in an approximate 50 
– 80% increase in cinacalcet bioavailability.  Increases in plasma cinacalcet concentration are similar, 
regardless of the fat content of the meal. 
 
After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of 
approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved 
within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase approximately 
linearly over the dose range of 30 to 180 mg once daily. At doses above 200 mg, the absorption was 
saturated probably due to poor solubility.  The pharmacokinetics of cinacalcet does not change over 
time.  The volume of distribution is high (approximately 1000 litres), indicating extensive distribution.  
Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood 
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Cinacalcet is metabolised by multiple enzymes, predominantly CYP3A4 and CYP1A2 (the 
contribution of CYP1A2 has not been characterised clinically).  The major circulating metabolites are 
inactive. 
 
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 and 
extensively metabolised by oxidation followed by conjugation.  Renal excretion of metabolites was 
the prevalent route of elimination of radioactivity.  Approximately 80% of the dose was recovered in 
the urine and 15% in the faeces. 
 
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 impairment did not notably affect the pharmacokinetics of 
cinacalcet. Compared to subjects with normal liver function, average AUC of cinacalcet was 
approximately 2-fold higher in subjects with moderate impairment and approximately 4-fold higher in 
subjects with severe impairment. The mean half-life of cinacalcet is prolonged by 33% and 70% in 
patients with moderate and severe hepatic impairment, respectively.  Protein binding of cinacalcet is 
not affected by impaired hepatic function. Because doses are titrated for each subject based on safety 
and efficacy parameters, no additional dose adjustment is necessary for subjects with hepatic 
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. 
 
Children and adolescents:  The pharmacokinetics of cinacalcet have not been studied in patients 
< 18 years of age. 
 
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 may 
change and dose adjustment may 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 
maximum human dose for secondary HPT (180 mg daily).  The non-teratogenic dose in rats was 4.4 
times, on an AUC basis, the maximum dose for secondary HPT.  There were no effects on fertility in 
males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small 
population of patients administered a maximum clinical dose of 360 mg daily would be approximately 
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.  Cinacalcet 
has been shown to cross the placental barrier in rabbits. 
 
Cinacalcet did not show any genotoxic or carcinogenic potential. Safety margins from the toxicology 
studies are small due to the dose-limiting hypocalcaemia observed in the animal models. Cataracts and 
lens opacities were observed in the repeat dose rodent toxicology and carcinogenicity studies, but were 

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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 serotonin transporter and KATP channels were found to be 7 and 
12 fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same 
experimental conditions.  The clinical relevance 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 
 
Pre-gelatinised starch (maize) 
Microcrystalline cellulose 
Povidone 
Crospovidone 
Magnesium stearate 
Colloidal anhydrous silica 
 
Tablet Coat 
 
Carnauba Wax 
Opadry II green:  (Lactose monohydrate, hypromellose, titanium dioxide (E171), 

glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172) 
Opadry clear:   (Hypromellose, macrogol) 
Opacode Black, printing ink: (Shellac glaze (shellac), iron oxide black (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Blister:  4 years. 
Bottle:  4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aclar/PVC/PVAc/Aluminium blister containing 14 tablets. Pack sizes of 1 blister (14 tablets), 2 
blisters (28 tablets), 6 blisters (84 tablets) per carton. 
 
High Density Polyethylene (HDPE) bottle with a desiccant canister and polyester coil, and a child-
resistant polypropylene cap with an induction seal, packed into a carton. Each bottle contains 30 
tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 

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7. MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/009-011 
EU/1/04/293/012 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
22 October 2004 
 
 
10. DATE OF REVISION OF THE TEXT 
 
  
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
(EMEA) http://www.emea.europa.eu/

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http://www.emea.europa.eu/


 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURING AUTHORISATION HOLDER 

RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OF THE MARKETING AUTHORISATION 
 

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A MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH 
RELEASE 

 
 
Name and address of the manufacturer responsible for batch release 
 
Amgen Europe B.V. 
Minervum 7061 
4817 ZK Breda 
The Netherlands 
 
 
B CONDITIONS OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to medical prescription 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable. 
 
• OTHER CONDITIONS 
 
Pharmacovigilance system 
 
The MAH must ensure that the system of pharmacovigilance, as described in version 3 presented in 
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and 
whilst the product is on the market. 
 
Risk Management Plan 
 
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in 
the Pharmacovigilance Plan, as agreed in version of 9 November 2007 of the Risk Management Plan 
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent 
updates of the RMP agreed by the CHMP. 
 
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the 
updated RMP should be submitted at the same time as the next Periodic Safety Update Report 
(PSUR). 
 
In addition, an updated RMP should be submitted  
- When new information is received that may impact on the current Safety Specification, 

Pharmacovigilance Plan or risk minimisation activities  
- Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being 

reached  
- At the request of the EMEA  
 
 

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ANNEX III 
 

LABELLING AND PACKAGING LEAFLET 
 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 30 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 30 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets  
28 tablets 
84 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/001 – carton of 14 tablets 
EU/1/04/293/002 – carton of 28 tablets 
EU/1/04/293/003 – carton of 84 tablets 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 30 mg tablet 
Cinacalcet  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
 
 
3. EXPIRY DATE 
 
EXP.: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 30 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 30 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/004 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BOTTLE 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 30 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 30 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/004 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 60 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 60 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets  
28 tablets 
84 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/005 – carton of 14 tablets 
EU/1/04/293/006 – carton of 28 tablets 
EU/1/04/293/007 – carton of 84 tablets 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 60 mg tablet 
Cinacalcet  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
 
 
3. EXPIRY DATE 
 
EXP.: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
 
 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 60 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 60 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/008  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BOTTLE 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 60 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 60 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/008  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 90 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 90 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 tablets  
28 tablets 
84 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/009 – carton of 14 tablets 
EU/1/04/293/010 – carton of 28 tablets 
EU/1/04/293/011 – carton of 84 tablets 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 90 mg tablet 
Cinacalcet  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
 
 
3. EXPIRY DATE 
 
EXP.: 
 
 
4. BATCH NUMBER 
 
Lot: 
 
 
5. OTHER 
 
 
 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
BOTTLE 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 90 mg film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 90 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/012  
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
CARTON FOR BOTTLE 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Parareg 90 mg  film-coated tablets 
Cinacalcet  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 90 mg of cinacalcet (as hydrochloride) 
 
 
3. LIST OF EXCIPIENTS 
 
Lactose monohydrate 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP.: 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/04/293/012 
 
 
13. BATCH NUMBER 
 
Lot: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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B. PACKAGE LEAFLET 

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PACKAGE LEAFLET : INFORMATION FOR THE USER 
 

Parareg 30 mg film-coated tablets 
Parareg 60 mg film-coated tablets 
Parareg 90 mg film-coated tablets 

Cinacalcet 
 

Read all of this leaflet carefully before you start taking this medicine. 
 
Keep this leaflet. You may need to read it again. 
 
If you have further questions, please ask your doctor or pharmacist. 
 
This medicine has been prescribed for you.  Do not pass it on to others. It may harm them, even if their 
symptoms are the same as yours. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
In this leaflet 
 
1. What Parareg is and what it is used for 
2. Before you take Parareg 
3. How to take Parareg 
4. Possible side effects 
5 How to store Parareg 
6. Further information 
 
 
1. WHAT PARAREG IS AND WHAT IT IS USED FOR 
 
Parareg works by controlling the levels of parathyroid hormone (PTH), calcium and phosphorous in 
your body.  It is used to treat problems with organs called parathyroid glands. The parathyroids are 
four small glands in the neck, near the thyroid gland, that produce parathyroid hormone (PTH).  
 
Parareg is used:  
• to treat secondary hyperparathyroidism in patients with kidney disease on dialysis. 
• to reduce high levels of calcium in the blood (hypercalcaemia) in patients with parathyroid 

cancer  
• to reduce high levels of calcium in the blood (hypercalcaemia) in patients with primary 

hyperparathyroidism who still have high calcium levels after removal of the parathyroid gland 
or when removal of the gland is not possible. 

 
In primary and secondary hyperparathyroidism too much PTH is produced by the parathyroids.  This 
can cause the loss of calcium in the bones, which can lead to bone pain and fractures, problems with 
blood and heart vessels, kidney stones, mental illness and coma.   
 
 
2. BEFORE YOU TAKE PARAREG 
 
Do not take Parareg: 
 
• DO NOT take Parareg if you are allergic (hypersensitive) to cinacalcet or any of the other 

ingredients of Parareg.   
 
Take special care with Parareg: 

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Before you start taking Parareg, tell your doctor if you have or have ever had  
 
• seizures (fits or convulsions).  The risk of having seizures is higher if you have had them 

before;   
• liver problems 
 
During treatment with Parareg, tell your doctor: 
• if you start or stop smoking, as this may affect the way Parareg works. 
 
Taking other medicines 
 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Please tell your doctor if you are taking the following medicines. 
 
These can affect how Parareg works: 
• medicines used to treat skin and fungal infections (ketoconazole, itraconazole, voriconazole); 
• antibiotics used to treat bacterial infections (telithromycin, rifampicin); 
• medicine used to treat HIV infection and AIDS (ritonavir). 
 
Parareg may affect how the following work: 
• medicines used to treat depression (amitriptyline, desipramine, nortriptyline, clomipramine and 

fluvoxamine); 
• medicines used to treat changes in heart rate (flecainide and propafenone);  
• medicine used to treat high blood pressure (metoprolol when given in heart failure) ,  
• antibiotic used to treat bacterial infections (ciprofloxacin). 
 
Taking Parareg with food and drink 
 
Parareg should be taken with or shortly after food. 
 
Pregnancy  and breast-feeding 
 
Always tell your doctor if you are pregnant or planning to become pregnant.  Parareg has not been 
tested in pregnant women. In case of pregnancy, your doctor may decide to modify your treatment, as 
Parareg might harm the foetus. .  
 
It is not known whether Parareg is excreted in human milk.  Your doctor will discuss with if you 
should discontinue either breast-feeding or treatment with Parareg.  
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
 
Parareg should not affect your ability to drive and use machines.  However, it is advisable to wait and 
see how you feel after taking Parareg and before driving or operating machinery. 
 
If you have an intolerance to some sugars 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product. 
 
 
3. HOW TO TAKE PARAREG 

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Children under the age of 18 must not take Parareg. 
 
Always take Parareg exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are unsure.  Your doctor will tell you how much Parareg you must take. 
 
Parareg must be taken orally, with or shortly after food.  The tablets must be taken whole and are not 
to be divided. 
 
Your doctor will take regular blood samples during treatment to monitor your progress and will adjust 
your dose if necessary. 
 
If you are being treated for secondary hyperparathyroidism 
 
The usual starting dose for Parareg is 30 mg (one tablet) once per day. 
 
If you are being treated for parathyroid cancer or primary hyperparathyroidism 
 
The usual starting dose for Parareg is 30 mg (one tablet) twice per day.   
 
If you take more Parareg than you should 
 
If you take more Parareg than you should you must contact your doctor immediately. 
 
If you forget to take Parareg 
 
Do not take a double dose to make up for forgotten doses.  
 
If you have forgotten a dose of Parareg, you should take your next dose as normal. 
 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Parareg can have side effects, although not everybody gets them. 
 
Very common side effects (seen in more than 1 in 10 people taking Parareg):  
• nausea and vomiting, these side effects are normally quite mild and do not last for long.  
 
Common side effects (seen in more than 1 in 100 people taking Parareg): 
• dizziness 
• numbness or tingling sensation (paraesthesia) 
• loss of appetite (anorexia) 
• muscle pain (myalgia) 
• weakness (asthenia) 
 rash 
 reduced testosterone levels 
•
•
 
Uncommon side effects (seen in more than 1 in 1000 people taking Parareg):  
• seizures 
• indigestion (dyspepsia) 
• diarrhoea 
• allergic reaction (hypersensitivity) 
 

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If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 
If you start to get numbness or tingling around the mouth, muscle aches or cramps and seizures you 
should tell you doctor immediately.   These may be signs that your calcium levels are too low 
(hypocalcaemia). 
 
After taking Parareg a very small number of patients with heart failure had worsening of their 
condition. Low blood pressure (hypotension) has also been seen in a very small number of these 
patients. As so few cases have been seen it is not known whether they are due to Parareg, or not. 
 
 
5. HOW TO STORE PARAREG 
 
Keep out of the reach and sight of children. 
 
This medicinal product does not require any special storage conditions 
 
Do not use Parareg after the expiry date which is stated on the outer carton and on the blister.  The 
expiry date refers to the last day of that month. 
(or) Do not use Parareg after the expiry date which is stated on the outer carton and on the bottle.    
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Parareg contains 
 
The active substance is cinacalcet.  Each film-coated tablet contains 30 mg, 60 mg or 90 mg of 
cinacalcet (as hydrochloride).  
 
The other ingredients are: 
• Pre-gelatinised maize starch 
• Microcrystalline cellulose 
• Povidone 
• Crospovidone 
• Magnesium stearate 
• Colloidal anhydrous silica.  
 
The tablets are coated with: 
• Carnauba wax 
• Opadry green (containing lactose monohydrate, hypromellose, titanium dioxide (E171), 

glycerol triacetate, FD&C Blue (E132), iron oxide yellow (E172)) 
• Opadry clear (containing hypromellose, macrogol) 
 
The printing ink contains: shellac glaze, iron oxide black (E172). 
 
What Parareg looks like and contents of the pack 
 
Parareg is a light green film-coated tablet.  They are oval-shaped and have “30”, “60” or “90” printed 
on one side and “Amgen” on the other side.  
 
Parareg is available in blisters of 30 mg, 60 mg or 90 mg film-coated tablets.  Each blister pack 
contains either 14, 28 or 84 tablets in a carton. 

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Parareg is available in bottles of 30 mg, 60 mg or 90 mg film-coated tablets, inside a carton.  Each 
bottle holds 30 tablets. 
 
Not all pack sizes may be marketed. 
  
Manufacturer: 
Amgen Europe B.V. 
Minervum 7061  
4817 ZK Breda 
The Netherlands 
 
Marketing Authorisation Holder: 
Dompé Biotec S.p.A. 
Via San Martino 12 
I-20122 Milan 
Italy 
 
This leaflet was last approved in  
 
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web 
site: http://www.emea.europa.eu/
 

 

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http://www.emea.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET