ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Mimpara 30 mg film-coated tablets
2.
Each tablet contains 30 mg cinacalcet (as hydrochloride).
Excipients:
Each 30 mg tablet contains 2.74 mg of lactose.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light green, oval, film-coated tablet marked “AMG” on one side and “30” on the other.
4.
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD)
on maintenance dialysis therapy.
Mimpara 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.
Secondary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every
2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH)
in dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH
levels should be assessed at least 12 hours after dosing with Mimpara.
Reference should be made to
current treatment guidelines.
PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara
.
PTH should be
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alter the
relationship between iPTH and biPTH.
2
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of
initiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serum
calcium should be measured approximately monthly. If serum calcium levels decrease below the
normal range, appropriate steps should be taken, including adjustment of concomitant therapy (see
section 4.4).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Parathyroid carcinoma and primary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose of Mimpara for adults is 30 mg twice per day. The dose of Mimpara
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was
90 mg four times daily.
Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara.
Once maintenance dose levels have been established, serum calcium should be measured every 2 to
3 months.
After titration to the maximum dose of Mimpara, serum calcium should be periodically
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of
Mimpara therapy should be considered (see section 5.1).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Hepatic impairment
No change in starting dose is necessary. Mimpara should be used with caution in
patients with
moderate to severe hepatic impairment and treatment should be closely monitored during dose titration
and continued treatment (see sections 4.4 and 5.2).
Method of administration
For oral use. It is recommended that Mimpara be taken with food or shortly after a meal, as studies
have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2).
Tablets should be taken whole and not divided.
Hypersensitivity to the active substance or to any of the excipients.
Seizures
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, 5% of the patients in
both the Mimpara and placebo groups reported a history of seizure disorder at baseline. In these
studies, seizures were observed in 1.4% of Mimpara treated patients and 0.4% of placebo-treated
3
patients. While the basis for the reported difference in seizure rate is not clear, the threshold for
seizures is lowered by significant reductions in serum calcium levels.
Hypotension and/or worsening heart failure
In post-marketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening
heart failure have been reported in patients with impaired cardiac function, in which a causal
relationship to cinacalcet could not be completely excluded and may be mediated by reductions in
serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated
patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving
cinacalcet or placebo.
Serum calcium
Mimpara 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 Mimpara, 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 Mimpara. 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 Mimpara, the dose of Mimpara and/or vitamin D
sterols should be reduced or therapy discontinued.
Testosterone levels
Testosterone levels are often below the normal range in patients with end-stage renal disease. In a
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.
An open-label extension of this study showed no further reductions in free and total testosterone
concentrations over a period of 3 years in Mimpara-treated patients. The clinical significance of these
reductions in serum testosterone is unknown.
Hepatic impairment
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to
severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these
patients and treatment should be closely monitored (see sections 4.2 and 5.2).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
4
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 Mimpara may be required if a patient receiving Mimpara initiates or
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin,
voriconazole, ritonavir) or inducer (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 1,500 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 Mimpara 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.
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).
5
Mimpara 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 Mimpara.
No studies on the effects on the ability to drive and use machines have been performed. However,
certain adverse reactions may affect the ability to drive and use machines (see section 4.8).
Secondary hyperparathyroidism
Data presented from controlled studies include 656 patients who received Mimpara and 470 patients
who received placebo for up to 6 months. The most commonly reported adverse reactions were nausea
and vomiting, occurring in 31% Mimpara and 19% placebo treated patients, and 27% Mimpara 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, 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 to < 1/10);
uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 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
Investigations
Common: hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4)
6
Parathyroid carcinoma and primary hyperparathyroidism
The safety profile of Mimpara 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
The following adverse reactions have been identified during postmarketing use of Mimpara, the
frequencies of which
cannot be estimated from available data:
•
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.
•
Allergic reactions, including angioedema and urticaria.
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis.
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for
overdose.
5.
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 C
max
.
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 Mimpara 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
7
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 Mimpara, 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 Mimpara 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 C
max
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
cells.
8
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.
Paediatric Population:
The pharmacokinetics of cinacalcet have been studied in 12 paediatric patients
(6-17 years) with CKD receiving dialysis following a single, oral, 15 mg dose. Mean AUC and C
max
values (23.5 (range 7.22 to 77.2) ng*hr/ml and 7.26 (range 1.80 to 17.4) ng/ml, respectively) were
within approximately 30% of the means for AUC and C
max
values observed in a single study in healthy
adults following a single 30 mg dose (33.6 (range 4.75 to 66.9) ng*hr/ml and 5.42 (range
1.41 to 12.7) ng/ml, respectively).
Due to the limited data in paediatric subjects, the potential for
higher exposures in the lighter/younger relative to heavier/older paediatric subjects for a given dose of
cinacalcet cannot be excluded. The pharmacokinetics in paediatric subjects after multiple doses has
not been studied.
Smoking:
Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of
CYP1A2- mediated metabolism. If a 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).
9
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
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, IC
50
values for the serotonin transporter and K
ATP
channels were found to be 7 and
12 fold greater, respectively, than the EC
50
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.
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)
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.
10
High Density Polyethylene (HDPE) bottle with a cotton 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.
7.
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8.
EU/1/04/292/001 – carton with 14 tablets
EU/1/04/292/002 – carton with 28 tablets
EU/1/04/292/003 – carton with 84 tablets
EU/1/04/292/004 – bottle with 30 tablets
9.
Date of first authorisation: 22 October 2004
Date of renewal of the authorisation:
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu/
11
1.
Mimpara 60 mg film-coated tablets.
2.
Each tablet contains 60 mg cinacalcet (as hydrochloride).
Excipients:
Each 60 mg tablet contains 5.47 mg of lactose.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light green, oval, film-coated tablets marked “AMG” on one side and “60” on the other.
4.
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD)
on maintenance dialysis therapy.
Mimpara 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.
Secondary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every
2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH)
in dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH
levels should be assessed at least 12 hours after dosing with Mimpara.
Reference should be made to
current treatment guidelines.
PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara
.
PTH should be
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alter the
relationship between iPTH and biPTH.
12
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of
initiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serum
calcium should be measured approximately monthly. If serum calcium levels decrease below the
normal range, appropriate steps should be taken, including adjustment of concomitant therapy (see
section 4.4).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Parathyroid carcinoma and primary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose of Mimpara for adults is 30 mg twice per day. The dose of Mimpara
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was
90 mg four times daily.
Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara.
Once maintenance dose levels have been established, serum calcium should be measured every 2 to
3 months.
After titration to the maximum dose of Mimpara, serum calcium should be periodically
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of
Mimpara therapy should be considered (see section 5.1).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Hepatic impairment
No change in starting dose is necessary. Mimpara should be used with caution in
patients with
moderate to severe hepatic impairment and treatment should be closely monitored during dose titration
and continued treatment (see sections 4.4 and 5.2).
Method of administration
For oral use. It is recommended that Mimpara be taken with food or shortly after a meal, as studies
have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2).
Tablets should be taken whole and not divided.
Hypersensitivity to the active substance or to any of the excipients.
Seizures
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, 5% of the patients in
both the Mimpara and placebo groups reported a history of seizure disorder at baseline. In these
studies, seizures were observed in 1.4% of Mimpara treated patients and 0.4% of placebo-treated
13
patients. While the basis for the reported difference in seizure rate is not clear, the threshold for
seizures is lowered by significant reductions in serum calcium levels.
Hypotension and/or worsening heart failure
In post-marketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening
heart failure have been reported in patients with impaired cardiac function, in which a causal
relationship to cinacalcet could not be completely excluded and may be mediated by reductions in
serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated
patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving
cinacalcet or placebo.
Serum calcium
Mimpara 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 Mimpara, 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 Mimpara. 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 Mimpara, the dose of Mimpara and/or vitamin D
sterols should be reduced or therapy discontinued.
Testosterone levels
Testosterone levels are often below the normal range in patients with end-stage renal disease. In a
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.
An open-label extension of this study showed no further reductions in free and total testosterone
concentrations over a period of 3 years in Mimpara-treated patients. The clinical significance of these
reductions in serum testosterone is unknown.
Hepatic impairment
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to
severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these
patients and treatment should be closely monitored (see sections 4.2 and 5.2).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
14
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 Mimpara may be required if a patient receiving Mimpara initiates or
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin,
voriconazole, ritonavir) or inducer (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 1,500 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 Mimpara 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.
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).
15
Mimpara 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 Mimpara.
No studies on the effects on the ability to drive and use machines have been performed. However,
certain adverse reactions may affect the ability to drive and use machines (see section 4.8).
Secondary hyperparathyroidism
Data presented from controlled studies include 656 patients who received Mimpara and 470 patients
who received placebo for up to 6 months. The most commonly reported adverse reactions were nausea
and vomiting, occurring in 31% Mimpara and 19% placebo treated patients, and 27% Mimpara 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, 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 to < 1/10);
uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 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
Investigations
Common: hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4)
16
Parathyroid carcinoma and primary hyperparathyroidism
The safety profile of Mimpara 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
The following adverse reactions have been identified during postmarketing use of Mimpara, the
frequencies of which
cannot be estimated from available data:
•
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.
•
Allergic reactions, including angioedema and urticaria.
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis.
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for
overdose.
5.
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 C
max
.
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 Mimpara 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
17
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 Mimpara, 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 Mimpara 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 C
max
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
cells.
18
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.
Paediatric Population:
The pharmacokinetics of cinacalcet have been studied in 12 paediatric patients
(6-17 years) with CKD receiving dialysis following a single, oral, 15 mg dose. Mean AUC and C
max
values (23.5 (range 7.22 to 77.2) ng*hr/ml and 7.26 (range 1.80 to 17.4) ng/ml, respectively) were
within approximately 30% of the means for AUC and C
max
values observed in a single study in healthy
adults following a single 30 mg dose (33.6 (range 4.75 to 66.9) ng*hr/ml and 5.42 (range
1.41 to 12.7) ng/ml, respectively).
Due to the limited data in paediatric subjects, the potential for
higher exposures in the lighter/younger relative to heavier/older paediatric subjects for a given dose of
cinacalcet cannot be excluded. The pharmacokinetics in paediatric subjects after multiple doses has
not been studied.
Smoking:
Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of
CYP1A2- mediated metabolism. If a 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).
19
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
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, IC
50
values for the serotonin transporter and K
ATP
channels were found to be 7 and
12 fold greater, respectively, than the EC
50
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.
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)
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 cotton coil, and a child-resistant polypropylene cap
with an induction seal, packed into a carton. Each bottle contains 30 tablets.
20
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8.
EU/1/04/292/005 – carton with 14 tablets
EU/1/04/292/006 – carton with 28 tablets
EU/1/04/292/007 – carton with 84 tablets
EU/1/04/292/008 – bottle with 30 tablets
9.
Date of first authorisation: 22 October 2004
Date of renewal of the authorisation:
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu/
21
1.
Mimpara 90 mg film-coated tablets.
2.
Each tablet contains 90 mg cinacalcet (as hydrochloride).
Excipients:
Each 90 mg tablet contains 8.21 mg of lactose.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet (tablet).
Light green, oval, film-coated tablets marked “AMG” on one side and “90” on the other.
4.
Treatment of secondary hyperparathyroidism (HPT) in patients with end-stage renal disease (ESRD)
on maintenance dialysis therapy.
Mimpara 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.
Secondary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every
2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH)
in dialysis patients of between 150-300 pg/ml (15.9-31.8 pmol/l) in the intact PTH (iPTH) assay. PTH
levels should be assessed at least 12 hours after dosing with Mimpara.
Reference should be made to
current treatment guidelines.
PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara
.
PTH should be
monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-
intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alter the
relationship between iPTH and biPTH.
22
During dose titration, serum calcium levels should be monitored frequently, and within 1 week of
initiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serum
calcium should be measured approximately monthly. If serum calcium levels decrease below the
normal range, appropriate steps should be taken, including adjustment of concomitant therapy (see
section 4.4).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Parathyroid carcinoma and primary hyperparathyroidism
Adults and elderly (> 65 years)
The recommended starting dose of Mimpara for adults is 30 mg twice per day. The dose of Mimpara
should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice
daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium
concentration to or below the upper limit of normal. The maximum dose used in clinical trials was
90 mg four times daily.
Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara.
Once maintenance dose levels have been established, serum calcium should be measured every 2 to
3 months.
After titration to the maximum dose of Mimpara, serum calcium should be periodically
monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of
Mimpara therapy should be considered (see section 5.1).
Children and adolescents
Mimpara is not indicated for use in children and adolescents due to a lack of data on safety and
efficacy (see section 5.2).
Hepatic impairment
No change in starting dose is necessary. Mimpara should be used with caution in
patients with
moderate to severe hepatic impairment and treatment should be closely monitored during dose titration
and continued treatment (see sections 4.4 and 5.2).
Method of administration
For oral use. It is recommended that Mimpara be taken with food or shortly after a meal, as studies
have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2).
Tablets should be taken whole and not divided.
Hypersensitivity to the active substance or to any of the excipients.
Seizures
In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, 5% of the patients in
both the Mimpara and placebo groups reported a history of seizure disorder at baseline. In these
studies, seizures were observed in 1.4% of Mimpara treated patients and 0.4% of placebo-treated
23
patients. While the basis for the reported difference in seizure rate is not clear, the threshold for
seizures is lowered by significant reductions in serum calcium levels.
Hypotension and/or worsening heart failure
In post-marketing safety surveillance, isolated, idiosyncratic cases of hypotension and/or worsening
heart failure have been reported in patients with impaired cardiac function, in which a causal
relationship to cinacalcet could not be completely excluded and may be mediated by reductions in
serum calcium levels. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated
patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving
cinacalcet or placebo.
Serum calcium
Mimpara 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 Mimpara, 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 Mimpara. 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 Mimpara, the dose of Mimpara and/or vitamin D
sterols should be reduced or therapy discontinued.
Testosterone levels
Testosterone levels are often below the normal range in patients with end-stage renal disease. In a
clinical study of ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in
the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment.
An open-label extension of this study showed no further reductions in free and total testosterone
concentrations over a period of 3 years in Mimpara-treated patients. The clinical significance of these
reductions in serum testosterone is unknown.
Hepatic impairment
Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to
severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these
patients and treatment should be closely monitored (see sections 4.2 and 5.2).
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption should not take this medicine.
24
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 Mimpara may be required if a patient receiving Mimpara initiates or
discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin,
voriconazole, ritonavir) or inducer (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 1,500 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 Mimpara 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.
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).
25
Mimpara 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 Mimpara.
No studies on the effects on the ability to drive and use machines have been performed. However,
certain adverse reactions may affect the ability to drive and use machines (see section 4.8).
Secondary hyperparathyroidism
Data presented from controlled studies include 656 patients who received Mimpara and 470 patients
who received placebo for up to 6 months. The most commonly reported adverse reactions were nausea
and vomiting, occurring in 31% Mimpara and 19% placebo treated patients, and 27% Mimpara 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, 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 to < 1/10);
uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 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
Investigations
Common: hypocalcaemia (see section 4.4), reduced testosterone levels (see section 4.4)
26
Parathyroid carcinoma and primary hyperparathyroidism
The safety profile of Mimpara 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
The following adverse reactions have been identified during postmarketing use of Mimpara, the
frequencies of which
cannot be estimated from available data:
•
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.
•
Allergic reactions, including angioedema and urticaria.
Doses titrated up to 300 mg once daily have been safely administered to patients receiving dialysis.
monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and
supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for
overdose.
5.
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 C
max
.
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 Mimpara 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
27
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 Mimpara, 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 Mimpara 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 C
max
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
cells.
28
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.
Paediatric Population:
The pharmacokinetics of cinacalcet have been studied in 12 paediatric patients
(6-17 years) with CKD receiving dialysis following a single, oral, 15 mg dose. Mean AUC and C
max
values (23.5 (range 7.22 to 77.2) ng*hr/ml and 7.26 (range 1.80 to 17.4) ng/ml, respectively) were
within approximately 30% of the means for AUC and C
max
values observed in a single study in healthy
adults following a single 30 mg dose (33.6 (range 4.75 to 66.9) ng*hr/ml and 5.42 (range
1.41 to 12.7) ng/ml, respectively).
Due to the limited data in paediatric subjects, the potential for
higher exposures in the lighter/younger relative to heavier/older paediatric subjects for a given dose of
cinacalcet cannot be excluded. The pharmacokinetics in paediatric subjects after multiple doses has
not been studied.
Smoking:
Clearance of cinacalcet is higher in smokers than in non-smokers, likely due to induction of
CYP1A2- mediated metabolism. If a 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).
29
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
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, IC
50
values for the serotonin transporter and K
ATP
channels were found to be 7 and
12 fold greater, respectively, than the EC
50
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.
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)
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 cotton coil, and a child-resistant polypropylene cap
with an induction seal, packed into a carton. Each bottle contains 30 tablets.
30
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
8.
EU/1/04/292/009 – carton with 14 tablets
EU/1/04/292/010 – carton with 28 tablets
EU/1/04/292/011 – carton with 84 tablets
EU/1/04/292/012 – bottle with 30 tablets
9.
Date of first authorisation: 22 October 2004
Date of renewal of the authorisation:
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu/
31
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
32
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
•
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
The MAH will submit PSURs on a yearly basis until otherwise requested by the CHMP.
33
ANNEX III
LABELLING AND PACKAGING LEAFLET
34
A. LABELLING
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BLISTER
1.
Mimpara 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.
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
36
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/001 – carton of 14 tablets
EU/1/04/292/002 – carton of 28 tablets
EU/1/04/292/003 – 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
mimpara 30
37
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
1.
Mimpara 30 mg tablet
Cinacalcet
2.
Amgen Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
38
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BOTTLE
1.
Mimpara 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.
One bottle containing 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
39
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/004
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
mimpara 30
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BOTTLE
1.
Mimpara 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.
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
41
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/004
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BLISTER
1.
Mimpara 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.
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
43
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/005 – carton of 14 tablets
EU/1/04/292/006 – carton of 28 tablets
EU/1/04/292/007 – 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
mimpara 60
44
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
1.
Mimpara 60 mg tablet
Cinacalcet
2.
Amgen Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
45
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BOTTLE
1.
Mimpara 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.
One bottle containing 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
46
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/008
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
mimpara 60
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BOTTLE
1.
Mimpara 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.
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
48
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/008
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BLISTER
1.
Mimpara 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.
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
50
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/009 – carton of 14 tablets
EU/1/04/292/010 – carton of 28 tablets
EU/1/04/292/011 – 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
mimpara 90
51
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
1.
Mimpara 90 mg tablet
Cinacalcet
2.
Amgen Europe B.V.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
52
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR BOTTLE
1.
Mimpara 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.
One bottle containing 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
53
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/012
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
mimpara 90
54
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
BOTTLE
1.
Mimpara 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.
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
55
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
EU/1/04/292/012
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
56
B. PACKAGE LEAFLET
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
Mimpara 30 mg film-coated tablets
Mimpara 60 mg film-coated tablets
Mimpara 90 mg film-coated tablets
Cinacalcet
Read all of this leaflet carefully before you start taking this medicine.
-
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 Mimpara is and what it is used for
2.
Before you take Mimpara
3.
How to take Mimpara
5.
How to store Mimpara
6.
Further information
1.
WHAT MIMPARA IS AND WHAT IT IS USED FOR
Mimpara 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).
Mimpara is used:
•
to treat secondary hyperparathyroidism in patients with serious kidney disease who need
dialysis to clear their blood of waste products.
•
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 glands.
“Primary” means that the hyperparathyroidism is not caused by any other condition and “secondary”
means that the hyperparathyroidism is caused by another condition, e.g., kidney disease. Both primary
and secondary hyperparathyroidism 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 MIMPARA
Do not take Mimpara:
•
DO NOT
take Mimpara if you are
allergic
(hypersensitive) to cinacalcet or any of the other
ingredients of Mimpara.
58
-
Keep this leaflet. You may need to read it again.
4.
Possible side effects
Take special care with Mimpara:
Children under the age of 18 must not take Mimpara.
Before you start taking Mimpara, 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
;
•
heart failure.
For additional information see section 4.
During treatment with Mimpara, tell your doctor:
•
if you start or stop smoking, as this may affect the way Mimpara 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 Mimpara 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).
Mimpara 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 Mimpara with food and drink
Mimpara 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. Mimpara has not been
tested in pregnant women. In case of pregnancy, your doctor may decide to modify your treatment, as
Mimpara might harm the unborn baby.
It is not known whether Mimpara is excreted in human milk. Your doctor will discuss with you if you
should discontinue either breast-feeding or treatment with Mimpara.
If you are pregnant or planning to become pregnant ask your doctor or pharmacist for advice before
taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Dizziness and
seizures have been reported by patients taking Mimpara. If you experience these, your ability to drive
or operate machinery may be affected.
59
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 MIMPARA
Always take Mimpara 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 Mimpara you must take.
Mimpara 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 Mimpara is 30 mg (one tablet) once per day.
If you are being treated for parathyroid cancer or primary hyperparathyroidism
The usual starting dose for Mimpara is 30 mg (one tablet) twice per day.
If you take more Mimpara than you should
If you take more Mimpara than you should you must contact your doctor immediately. Possible signs
of overdose include numbness or tingling around the mouth, muscle aches or cramps and seizures.
If you forget to take Mimpara
Do not take a double dose to make up for forgotten doses.
If you have forgotten a dose of Mimpara, 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, Mimpara can have side effects, although not everybody gets them.
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).
Very common side effects
(seen in more than 1 in 10 people taking Mimpara):
•
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 Mimpara):
•
dizziness
•
numbness or tingling sensation (paraesthesia)
•
loss of appetite (anorexia)
•
muscle pain (myalgia)
•
weakness (asthenia)
60
•
rash
•
reduced testosterone levels.
Uncommon side effects
(seen in more than 1 in 1000 people taking Mimpara):
•
seizures
•
indigestion (dyspepsia)
•
diarrhoea
•
allergic reaction (hypersensitivity).
Frequency not known
•
Hives (urticaria).
•
Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or
breathing (angioedema).
After taking Mimpara 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 Mimpara, or not.
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.
5.
HOW TO STORE MIMPARA
Keep out of the reach and sight of children.
Do not use Mimpara 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 Mimpara after the expiry date which is stated on the outer carton and on the bottle.
This medicinal product does not require any special storage conditions.
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 Mimpara 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)
61
What Mimpara looks like and contents of the pack
Mimpara is a light green film-coated tablet. They are oval-shaped and have “30”, “60” or “90”
marked on one side and “AMG” on the other side.
Mimpara 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.
Mimpara 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.
Marketing Authorisation Holder and Manufacturer:
Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
s.a. Amgen n.v.
Tel/Tél: +32 (0)2 7752711
Luxembourg/Luxemburg
s.a. Amgen
Belgique/Belgien
Tel/Tél: +32 (0)2 7752711
България
Amgen Bulgaria EOOD
Тел: +359 (0) 2 805 7020
Magyarország
Amgen Kft.
Tel. : +36 1 35 44 700
Česká republika
Amgen s.r.o
Tel : +420 2 21 773 500
Malta
Amgen B.V.
The Netherlands
Tel : +31 (0) 76 5732500
Danmark
Amgen filial af Amgen AB, Sverige
Tlf: +45 39617500
Nederland
Amgen B.V.
Tel: +31 (0) 76 5732500
Deutschland
AMGEN GmbH
Tel: +49 (0)89 1490960
Norge
Amgen AB
Tel: +47 23308000
Eesti
Amgen Switzerland AG Eesti filiaal
Tel: +372 5125 501
Österreich
Amgen GmbH
Tel: +43 (0) 1 50 217
Ελλάδα
Genesis Pharma S.A.
Τηλ.: +30 210 8771500
Polska
Amgen Sp. z o.o.
Tel.: +48 22 581 3000
España
Amgen S.A.
Tel: +34 93 600 19 00
Portugal
AMGEN Biofarmacêutica, Lda.
Tel: +351 21 4220550
62
France
Amgen S.A.S
Tél: +33 (0)1 40 88 27 00
România
Mediplus Exim SRL
Tel.: +4021 301 74 74
Ireland
Amgen Limited
United Kingdom
Tel:
+44 (0)1223 420305
Suomi/Finland
Amgen AB, sivuliike Suomessa/Amgen AB, filial
i Finland
Puh/Tel: +358 (0)9 54900500
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Amgen Switzerland AG, Slovakia
Tel : +42 1 25939 6456
Italia
Amgen Dompé S.p.A.
Tel: +39 02 6241121
Slovenija
AMGEN zdravila d.o.o.
Tel : +386 1 585 1767
Kύπρος
Genesis Pharma (Cyprus) Ltd
Τηλ.: +357 22 76 99 46
Sverige
Amgen AB
Tel: +46 (0)8 6951100
Latvija
Amgen Switzerland AG Rīgas filiāle
Tel : +371 29284 807
United Kingdom
Amgen Limited
Tel: +44 (0)1223 420305
Lietuva
Amgen Switzerland AG Vilniaus filialas
Tel.: +370 6983 6600
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/
.
63
Source: European Medicines Agency
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