cinacalcet: prescribing information – dosing, contraindications, interactions, side effects

Secondary hyperparathyroidism

Adults
Treatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.

Paediatric population
Treatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy (see section 4.4).

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

Parathyroid carcinoma and primary hyperparathyroidism in adults

Reduction of hypercalcaemia in adult 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.

Posology

Secondary hyperparathyroidism

Adults and elderly (> 65 years)
The recommended starting dose for adults is 30 mg once per day. Cinacalcet 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 cinacalcet. Reference should be made to current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of cinacalcet. 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 cinacalcet does not alter the relationship between iPTH and biPTH.

Dose adjustment based on serum calcium levels
Corrected serum calcium should be measured and monitored and should be at or above the lower limit of the normal range prior to administration of first dose of cinacalcet (see section 4.4). The normal calcium range may differ depending on the methods used by your local laboratory.

During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment of cinacalcet. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. In the event that corrected serum calcium levels fall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcaemia occur the following management is recommended:

Corrected Serum calcium level or clinical symptoms of hypocalcaemia
Recommendations
< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL
(1.9 mmol/L), or in the presence of clinical symptoms of hypocalcaemia
Calcium-containing phosphate binders, vitamin D sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium according to clinical judgment.
< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL
(1.9 mmol/L) or persistent symptoms of hypocalcaemia despite attempts to increase serum calcium Reduce or withhold dose of cinacalcet.
≤ 7.5 mg/dL (1.9 mmol/L) or persistent symptoms of hypocalcaemia and Vitamin D cannot be increased Withhold administration of cinacalcet until serum calcium levels reach 8.0 mg/dL (2.0 mmol/L) and/or symptoms of hypocalcaemia have resolved.
Treatment should be reinitiated using the next lowest dose of cinacalcet.

Paediatric population

Corrected serum calcium should be in the upper range of, or above, the age-specified reference interval prior to administration of first dose of cinacalcet, and closely monitored (see section 4.4). The normal calcium range differs depending on the methods used by your local laboratory and the age of the child/patient.

The recommended starting dose for children aged ≥ 3 years to < 18 years is ≤ 0.20 mg/kg once daily based on the patient’s dry weight (see table 1).

The dose can be increased to achieve a desired target iPTH range. The dose should be increased sequentially through available dose levels (see table 1) no more frequently than every 4 weeks. The dose can be increased up to a maximum dose of 2.5 mg/kg/day, not to exceed a total daily dose of 180 mg.
Table 1. Cinacalcet daily dose in paediatric patients

Patient dry weight (kg)

Starting dose (mg)
Available sequential dose levels (mg)
10 to < 12.5
1, 2.5, 5, 7.5, 10 and 15
≥ 12.5 to < 25

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypocalcaemia (see sections 4.2 and 4.4).

a)
Summary of the safety profile

Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism

Based on available data from patients receiving cinacalcet in placebo-controlled studies and single- arm studies the most commonly reported adverse reactions were nausea and vomiting. 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 and vomiting.

b)
Tabulated list of adverse reactions

Adverse reactions, considered at least possibly attributable to cinacalcet treatment in the placebo- controlled studies and single-arm studies based on best-evidence assessment of causality 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).

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

MedDRA system organ class
Frequency
Adverse reaction
Immune system disorders
Common*
Hypersensitivity reactions
Metabolism and nutrition disorders
Common
Anorexia Decreased appetite
Nervous system disorders
Common
Seizures†
Dizziness
Paraesthesia
Headache
Cardiac disorders
Not known*
Worsening heart failure†
QT prolongation and ventricular arrhythmia secondary to hypocalcaemia†
Vascular disorders
Common
Hypotension
Respiratory, thoracic and mediastinal disorders
Common
Upper respiratory infection
Dyspnoea
Cough
Gastrointestinal disorders
Very common
Nausea
Vomiting

MedDRA system organ class
Frequency
Adverse reaction
Common
Dyspepsia
Diarrhoea
Abdominal pain
Abdominal pain – upper
Constipation
Skin and subcutaneous tissue disorders
Common
Rash
Musculoskeletal and connective tissue disorders
Common
Myalgia
Muscle spasms
Back pain
General disorders and administration site conditions
Common
Asthenia
Investigations
Common
Hypocalcaemia†
Hyperkalaemia
Reduced testosterone levels†
†see section 4.4
*see section “Description of selected adverse reactions”

c)
Description of selected adverse reactions

Hypersensitivity reactions
Hypersensitivity reactions including angioedema and urticaria have been identified during post- marketing use of cinacalcet. The frequencies of the individual preferred terms including angioedema and urticaria cannot be estimated from available data.

Hypotension and/or worsening heart failure
There have been reports of idiosyncratic cases of hypotension and/or worsening heart failure in cinacalcet-treated patients with impaired cardiac function in post-marketing safety surveillance, the frequencies of which cannot be estimated from available data.

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia
QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been identified during post-marketing use of cinacalcet, the frequencies of which cannot be estimated from available data (see section 4.4).

d)
Paediatric population

The safety of cinacalcet for the treatment of secondary HPT in paediatric patients with ESRD receiving dialysis was evaluated in two randomised controlled studies and one single-arm study (see section 5.1). Among all paediatric subjects exposed to cinacalcet in clinical studies a total of 19 subjects (24.1%; 64.5 per 100 subject years) had at least one adverse event of hypocalcaemia. A fatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (see section 4.4).

Cinacalcet should be used in paediatric patients only if the potential benefit justifies the potential risk.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Serum calcium

Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in adult and paediatric patients treated with cinacalcet. Manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and convulsions. Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia secondary to hypocalcaemia.
Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet (see section 4.8). Caution is advised in patients with other risk factors for QT prolongation such as patients with known congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation.

Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia (see section 4.2). Serum calcium should be measured within 1 week after initiation or dose adjustment of cinacalcet.

Adults
Cinacalcet treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range.

In CKD patients receiving dialysis who were administered cinacalcet, approximately 30% of patients had at least one serum calcium value less than 7.5 mg/dL (1.9 mmol/L).

Paediatric population

Cinacalcet should only be initiated for the treatment of secondary HPT in children ≥ 3 years old with ESRD on maintenance dialysis therapy, in whom secondary HPT is not adequately controlled with standard of care therapy, where serum calcium is in the upper range of, or above, the age-specified reference interval.

Closely monitor serum calcium levels (see section 4.2) and patient compliance during treatment with cinacalcet. Do not initiate cinacalcet or increase the dose if non-compliance is suspected.

Prior to initiating cinacalcet and during treatment, consider the risks and benefits of treatment and the ability of the patient to comply with the recommendations to monitor and manage the risk of hypocalcaemia.

Inform paediatric patients and/or their caregivers about the symptoms of hypocalcaemia and about the importance of adherence to instructions about serum calcium monitoring, and posology and method of administration.

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

Seizures

Cases of seizures have been reported in patients treated with cinacalcet (see section 4.8). The threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving cinacalcet, particularly in patients with a history of a seizure disorder.

Hypotension and/or worsening heart failure

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 (see section 4.8).

Co-administration with other medicinal products

Administer cinacalcet with caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium (see section 4.5).

Patients receiving cinacalcet should not be given etelcalcetide. Concurrent administration may result in severe hypocalcaemia.

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 cinacalcet, the dose of cinacalcet 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 adult ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the cinacalcet-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. An open-label extension of this study showed no further reductions in free and total testosterone concentrations over a period of 3 years in cinacalcet-treated patients. 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), cinacalcet should be used with caution in these patients and treatment should be closely monitored (see sections 4.2 and 5.2).

Medicinal products known to reduce serum calcium

Concurrent administration of other medicinal products known to reduce serum calcium and cinacalcet may result in an increased risk of hypocalcaemia (see section 4.4). Patients receiving cinacalcet should not be given etelcalcetide (see section 4.4).

Effect of other medicinal products 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 cinacalcet may be required if a patient receiving cinacalcet initiates or discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g. rifampicin) of this enzyme.

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 (2,400 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 medicinal products

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 cinacalcet is administered with individually titrated, narrow therapeutic index substances that are predominantly metabolised by CYP2D6 (e.g. flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine).

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.

Dextromethorphan: Multiple doses of 50 mg cinacalcet increased the AUC of 30 mg dextromethorphan (metabolised primarily by CYP2D6) by 11-fold 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 medicines that are metabolised by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus.

Pregnancy

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).

Cinacalcet should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is not known whether cinacalcet is excreted 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 cinacalcet.

Fertility

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

Dizziness and seizures, which may have major influence on the ability to drive and use machines, have been reported by patients taking cinacalcet (see section 4.4).

Doses titrated up to 300 mg once daily have been administered to adult patients receiving dialysis without adverse outcome. A daily dose of 3.9 mg/kg was prescribed to a paediatric patient receiving dialysis in a clinical study with subsequent mild stomach ache, nausea and vomiting.

Overdose of cinacalcet may lead to hypocalcaemia. In the event of overdose, 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 overdose.

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

The calcium sensing receptor on the surface of the chief cell of the parathyroid gland is the principal regulator of PTH 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.

After steady state is reached, serum calcium concentrations remain constant over the dosing interval.

Secondary hyperparathyroidism

Adults
Three, 6-month, double-blind, placebo-controlled clinical studies were conducted in ESRD patients with uncontrolled secondary HPT receiving dialysis (n = 1,136). 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 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

Absorption

After oral administration of cinacalcet, 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 cinacalcet 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.

At doses above 200 mg, the absorption was saturated probably due to poor solubility.

Distribution

The volume of distribution is high (approximately 1,000 litres), indicating extensive distribution.
Cinacalcet is approximately 97% bound to plasma proteins and distributes minimally into red blood cells.

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 levels of cinacalcet are achieved within 7 days with minimal accumulation. The pharmacokinetics of cinacalcet does not change over time.

Biotransformation

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.

Elimination

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.

Linearity/non-linearity