Cinacalcet

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.

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).

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. The effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not been studied. Dose adjustment may be necessary when concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

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.

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.

Multiple doses of 50 mg cinacalcet increased the AUC of 30 mg dextromethorphan (metabolised primarily by CYP2D6) by 11-fold in CYP2D6 extensive metabolisers.

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

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. Dose adjustment may be necessary if a patient starts or stops smoking.

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.

Cases of seizures have been reported in patients treated with cinacalcet. 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.

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. Cinacalcet 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 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.

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.

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:

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

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 "Description of selected adverse reactions"

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.

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. 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.

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