Parareg - summary of medicine characteristics

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30 mg cinacalcet (as hydrochloride).

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet (tablet).

30 mg: Light green, oval, film-coated tablets marked “AMGEN” on one side an

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Treatment of secondary hyperparathyroidism (HPT) in patie on maintenance dialysis therapy.

Parareg may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5.1).

Reduction of hypercalcaemia in patients wi

• • parathyroid carcinoma.
• • primary HPT for whom parat

levels (as defined by relevan clinically appropriate or i

For oral use. It is reco ded that Parareg be taken with food or shortly after a meal, as studies have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2). Tablets should be taken whole and not divided.

in starting dose is necessary. Parareg should be used with caution in patients with moderate ere hepatic impairment and treatment should be closely monitored during dose titration and continued treatment (see sections 4.4 and 5.2).

Secondary Hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose for adults is 30 mg once per day. Parareg should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in dialysis patients of between 150–300 pg/ml (15.9–31.8 pmol/l) in the intact PTH (iPTH) assay. PTH levels should be assessed at least 12 hours after dosing with Parareg. Reference should be made to current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Parareg. PTH should be monitored approximately every 1–3 months during maintenance. Either the intact PTH (iPTH) or biointact PTH (biPTH) may be used to measure PTH levels; treatment with Parareg does not alter the relationship between iPTH and biPTH.

Information regarding the pharmacokinetic/phar­macodynamic (PK/PD) profile of cinacalcet is given in section 5.1

During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment of Parareg. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. If serum calcium levels decrease below the normal range, appropriate steps should be taken (see section 4.4). Concomitant therapy with phosphate binders and/or vitamin D sterols should be adjusted as appropriate.

Children and adolescents

Safety and efficacy have not been established in patients below the age of 18 y

Parathyroid Carcinoma and Primary Hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose of Parareg for adults is 30 mg twice per day. The dosage of Parareg should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 90 mg four times daily.

fter initiation or dose adjustment of Parareg. Once , serum calcium should be measured every 2 to e of Parareg, serum calcium should be periodically in serum calcium are not maintained, discontinuation of

Children and adolescents

t been established in patients below the age of 18 years.

to the active substance or to any of the excipients.

ial warnings and precautions for use

Seizures

In three clinical studies of Chronic Kidney Disease (CKD) patients on dialysis, five percent of the patients in both the Parareg and placebo groups reported a history of seizure disorder at baseline. In these studies, seizures were observed in 1.4% of Parareg treated patients and 0.4% of placebo-treated patients. While the basis for the reported difference in seizure rate is not clear, the threshold for seizures is lowered by significant reductions in serum calcium levels.

Hepatic Insufficiency

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

Interactions

Caution should be exercised when administering Parareg concomitantly with strong inhibitors or inducers of CYP3A4 and/or CYP1A2. Dose adjustment of Parareg may be necessary (see section 4.5).

Caution should be exercised when Parareg is administered with individually titrated, narrow therapeutic index medications that are predominantly metabolised by CYP2D6. Dose adjustments of concomitant medications may be necessary (see section 4.5).

Plasma levels of cinacalcet may be lower in smokers due to induction of CYP1A2-mediated metabolism. Dose adjustments may be necessary if a patient starts or stops smoking during cinacalcet treatment (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medications on cinacalcet

Cinacalcet is metabolised in part by the enzyme CYP3A4. Co-administration of 200 mg bid ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet

levels. Dose adjustment of Parareg may be required if a patient receiving Parareg initiates or discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (eg rifampicin) of this enzyme (see Section 4.4).

In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induce the clearance of cinacalcet was observed to be 36–38% higher in smokers than non-s effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plas been studied. Dose adjustment may be necessary if a patient starts or stops smok concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

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

Sevelamer : Co-administration of sevelamer (2400 mg ti cinacalcet.

Pantoprazole : Co-administration of pantoprazole (80 mg od) did not alter the pharmacokinetics of cinacalcet. r>

Effect of cinacalcet on other medications

nzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor mitant medicinal products may be required when Parareg is arrow therapeutic index substances that are predominantly nide, propafenone, metoprolol given in heart failure, desipramine,

Desipramine : Concurrministration 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.

iple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics 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 autoinduction 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.

4.6 Pregnancy and lactation

There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, parturition or postnatal development. No embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3). Parareg should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performe

4.8 Undesirable effects

Secondary Hyperparathyro­idism

Data presented from controlled studies include 656 patients who received Parareg and 470 patients who received placebo for up to 6 months. The most commonly reported undesirable effects were nausea and vomiting, occurring in 31% Parareg and 19% placebo treated patients, and 27% Parareg and 15% placebo treated patients, respectively. Nausea and vomiting were mild to moderate in severity and transient in nature in the undesirable effects was mainly due to placebo; 4% cinacalcet).

s considered at least possibly attributable to cinacalcet

t of causality and reported in excess of placebo in doublefollowing convention: very common (> 1/10); common

1/100); rare (> 1/10,000, < 1/1,000); very rare

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)

Parathyroid Carcinoma and Primary Hyperparathyro­idism

The safety profile of Parareg in these patient populations is generally consistent with that seen in patients with Chronic Kidney Disease. The most frequent ADRs in these patient populations were nausea and vomiting.

Post-marketing Experience

There have been reports of isolated, idiosyncratic cases of hypotension and/or worsening heart fai in cinacalcet-treated patients with impaired cardiac function in post marketing safety surveillance.

4.9 Overdose

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

Overdosage of Parareg may lead to hypocalcaemia. In the event of overdosage, patients should be monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for overdosage.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anti-parathyroi

The calcium sensing receptor on ace of the chief cell of the parathyroid gland is the principal regulator of PTH secretion. Cilcet is a calcimimetic agent which directly lowers PTH levels by increasing the sensitivity of thcium sensing receptor to extracellular calcium. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.

levels correlate with cinacalcet concentration. Soon after dosing, PTH begins to ir at approximately 2 to 6 hours postdose, corresponding with cinacalcet Cmax.

cet levels begin to decline, PTH levels increase until 12 hours post-dose, and sion remains approximately constant to the end of the once-daily dosing interval.

arareg clinical trials were measured at the end of the dosing interval.

eady 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 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 mark specific alkaline phosphatase, N-telopeptide, bone turnover and bone fibrosis). In post-hoc pooled data from 6 and 12 months clinical studies, Kaplan-Meier estimates of bone frac parathyroidectomy were lower in the cinacalcet group compared with the control group

Investigational studies in patients with CKD and secondary HPT not undergoin cinacalcet reduced PTH levels to a similar extent as in patients with ESRD receiving dialysis. However, efficacy, safety, optimal doses and treatment established in treatment of predialytic renal failure patients. These studies undergoing dialysis treated with cinacalcet have an increased risk for hypocalcaemia compared with cinacalcet-treated ESRD patients receiving dialysis, which may e to lower baseline calcium levels.

Based on between-study comparisons, the absolute bioavailability of cinacalcet in fasted subjects has been estimated to be about 20–25%. Administration of Parareg with food results in an approximate 50 – 80% increase in cinacalcet bioavailability. Increases in plasma cinacalcet concentration are similar, regardless of the fat content of the meal.

After absorption, cinacalcet concentrations decline in a biphasic fashion with an initial half-life of approximately 6 hours and a terminal half-life of 30 to 40 hours. Steady state drug levels are achieved within 7 days with minimal accumulation. The AUC and Cmax of cinacalcet increase approximately linearly over the dose range of 30 to 180 mg once daily. At doses above 200 mg, the absorption was saturated probably due to poor solubility. The pharmacokinetics of cinacalcet does not change over time. The volume of distribution is high (approximately 1000 litres), indicating extensive distribution. Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.

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

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 impairme d approximately 4-fold higher in subjects with severe impairment. The mean half-life of cinacalcet irolonged by 33% and 70% in patients with moderate and severe hepatic impairment, resp. Protein binding of cinacalcet is not affected by impaired hepatic function. Because doses aritrated 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).

y data

Cinacalcet was not teratogenic in rabbits when given at a dose of 0.4 times, on an AUC basis, the maximum human dose for secondary HPT (180 mg daily). The non-teratogenic dose in rats was 4.4 times, on an AUC basis, the maximum dose for secondary HPT. There were no effects on fertility in males or females at exposures up to 4 times a human dose of 180 mg/day (safety margins in the small population of patients administered a maximum clinical dose of 360 mg daily would be approximately half those given above).

In pregnant rats, there were slight decreases in body weight and food consumption at the highest dose. Decreased foetal weights were seen in rats at doses where dams had severe hypocalcaemia. Cinacalcet has been shown to cross the placental barrier in rabbits.

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

In in vitro studies, IC50 values for the serotonin transporter and KATP channels were found to be 7 and 12 fold greater, respectively, than the EC50 for the calcium-sensing receptor obtained under the same experimental conditions. The clinical relevance is unknown, however, the potential for cinacalcet to act on these secondary targets cannot be fully excluded.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

re and contents of container

6.6 Special precautions for disposal

7. MARKETING AUTHORISATION HOLDER

Dompé Biotec S.p.A.

Via San Martino 12

I-20122 Milan

Italy

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/293/001–003

EU/1/04/293/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHO

22 October 2004

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the (EMEA)