Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypocalcaemia (see sections 4.2 and 4.4).
Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in adult and paediatric patients treated with Mimpara. 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 Mimpara.
Mimpara 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 Mimpara, approximately 30% of patients had at least one serum calcium value less than 7.5 mg/dL (1.9 mmol/L).
Mimpara 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.
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.
Cases of seizures have been reported in patients treated with Mimpara (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 Mimpara, particularly in patients with a history of a seizure disorder.
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).
Administer Mimpara with caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium (see section 4.5).
Patients receiving Mimpara should not be given etelcalcetide. Concurrent administration may result in severe hypocalcaemia.
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 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 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.
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).
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Concurrent administration of other medicinal products known to reduce serum calcium and Mimpara may result in an increased risk of hypocalcaemia (see section 4.4). Patients receiving Mimpara should not be given etelcalcetide (see section 4.4).
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 (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.
Co-administration of calcium carbonate (single 1,500 mg dose) did not alter the pharmacokinetics of cinacalcet.
Co-administration of sevelamer (2,400 mg tid) did not affect the pharmacokinetics of cinacalcet.
Co-administration of pantoprazole (80 mg od) did not alter the pharmacokinetics of cinacalcet.
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, desipramine, nortriptyline, clomipramine).
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.
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.
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.
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). 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.
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 Mimpara (see section 4.4).
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.
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:
Common*: Hypersensitivity reactions
Common: Anorexia, Decreased appetite
Common: Seizures†, Dizziness, Paraesthesia, Headache
Not known*: Worsening heart failure†, QT prolongation and ventricular arrhythmia, secondary to hypocalcaemia†
Common: Hypotension
Common: Upper respiratory infection, Dyspnoea, Cough
Very common: Nausea, Vomiting
Common: Dyspepsia, Diarrhoea, Abdominal pain, Abdominal pain – upper, Constipation
Common: Rash
Common: Myalgia, Muscle spasms, Back pain
Common: Asthenia
Common: Hypocalcaemia†, Hyperkalaemia, Reduced testosterone levels†
† see section 4.4
* see section c
Hypersensitivity reactions including angioedema and urticaria have been identified during post-marketing use of Mimpara. The frequencies of the individual preferred terms including angioedema and urticaria cannot be estimated from available data.
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 have been identified during post-marketing use of Mimpara, the frequencies of which cannot be estimated from available data (see section 4.4).
The safety of Mimpara 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).
Mimpara should be used in paediatric patients only if the potential benefit justifies the potential risk.
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.
Not applicable.
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