4.1. Therapeutic indications

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

Cinacalcet Mylan 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 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.

4.2. Posology and method of administration

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:

Table 1. Dose recommendations based on serum calcium levels

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.

Corrected serum calcium level or clinical symptoms of hypocalcaemia

Recommendations

≤ 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

Cinacalcet Mylan is not indicated for use in children and adolescents. Other pharmaceutical forms may be available for this population.

Switch from etelcalcetide to Cinacalcet Mylan

The switch from etelcalcetide to Cinacalcet Mylan and the appropriate wash out period has not been studied in patients. In patients who have discontinued etelcalcetide, Cinacalcet Mylan should not be initiated until at least three subsequent haemodialysis sessions have been completed, at which time serum calcium should be measured. Ensure serum calcium levels are within the normal range before Cinacalcet Mylan is initiated (see sections 4.4 and 4.8).

Parathyroid carcinoma and primary hyperparathyroidism:

Adults and elderly (> 65 years)

The recommended starting dose of Cinacalcet Mylan for adults is 30 mg twice per day. The dose of cinacalcet 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 cinacalcet. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose of cinacalcet, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of cinacalcet therapy should be considered (see section 5.1).

Paediatric population

The safety and efficacy of cinacalcet in children for the treatment of parathyroid carcinoma and primary hyperparathyroidism have not been established. No data are available.

Hepatic impairment

No change in starting dose is necessary. Cinacalcet 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.

Tablets should be taken whole and should not be chewed, crushed or divided.

It is recommended that Cinacalcet Mylan 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).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia (see sections 4.2 and 4.4).

4.4. Special warnings and precautions for use

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.

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

In Chronic Kidney Disease (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).

CKD patients not on dialysis

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.

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 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).

4.5. Interaction with other medicinal products and other forms of interaction

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, twice daily 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, three times a day) did not affect the pharmacokinetics of cinacalcet.

Pantoprazole

Co-administration of pantoprazole (80 mg, once daily) 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 metabolized by CYP3A4 and CYP3A5, such as certain immunosuppressants, including ciclosporin and tacrolimus.

4.6. Fertility, pregnancy and lactation

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 Mylan 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 Mylan.

Fertility

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

4.7. Effects on ability to drive and use machines

Cinacalcet may have major influence on the ability to drive and use machines, since dizziness and seizures have been reported by patients taking this medicinal product (see section 4.4).

4.8. Undesirable effects

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); not known (cannot be estimated from the available data).

Table 2.Incidence of adverse reactions from controlled clinical studies and post-marketing experience

System organ class

Very Common

Common

Not known

Immune system disorders

Hypersensitivity reactions*

Metabolism and nutrition disorders

Anorexia

Decreased appetite

Nervous system disorders

Seizures†

Dizziness

Paraesthesia

Headache

Cardiac disorders

Worsening heart failure* †

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia* †

Vascular disorders

Hypotension

Respiratory, thoracic and mediastinal disorders

Upper respiratory infection

Dyspnoea

Cough

Gastrointestinal disorders

Nausea

Vomiting

Dyspepsia

Diarrhoea

Abdominal pain

Abdominal pain - upper

Constipation

Skin and subcutaneous tissue disorders

Rash

Musculoskeletal and connective tissue disorders

Myalgia

Muscle spasms

Back pain

General disorders and administration site conditions

Asthenia

Investigations

Hypocalcaemia†

Hyperkalaemia

Reduced testosterone levels†

* see section description of selected adverse reactions

† see section 4.4

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).

Paediatric population

Cinacalcet Mylan is not indicated for use in paediatric patients. The safety and efficacy of cinacalcet in the paediatric population have not been established. A fatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (see section 4.4).

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 Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard

Or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Doses titrated up to 300 mg once daily have been administered to patients receiving dialysis without adverse outcome.

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.