Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Serum calcium

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

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 Teva. Once the maintenance dose has been established, serum calcium should be measured approximately monthly.

In the event that serum calcium levels fall below 8.4 mg/dl (2.1 mmol/l) and/or symptoms of hypocalcaemia occur the following management is recommended:

Serum calcium value or clinical symptoms of                Recommendations hypocalcaemia
< 8.4 mg/dl (2.1 mmol/l) and>7.5 mg/dl (1.9                Calcium-containing phosphate binders, vitamin D mmol/l), or in the presence of clinical symptoms           sterols and/or adjustment of dialysis fluid calcium of hypocalcaemia                                           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              Reduce or withhold dose of Cinacalcet Teva.
mmol/l) or persistent symptoms of hypocalcaemia despite attempts to increase serum calcium
≤ 7.5 mg/dl (1.9 mmol/l) or persistent symptoms Withhold administration of Cinacalcet Teva until of hypocalcemia and Vitamin D cannot be         serum calcium levels reach 8.0 mg/dl (2.0 increased                                       mmol/l) and/or symptoms of hypocalcaemia have resolved.
Treatment should be reinitiated using the next lowest dose of Cinacalcet Teva.

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

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

In clinical studies seizures were observed in 1.4% of cinacalcet treated patients and 0.7% 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.

Hypotension and/or worsening heart failure

In post-marketing safety surveillance, isolated, idiosyncratic 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. Clinical trial data showed hypotension occurred in 7% of cinacalcet-treated patients, 12% of placebo-treated patients, and heart failure occurred in 2% of patients receiving cinacalcet or placebo.

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 Teva, the dose of Cinacalcet Teva 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 Teva should be used with caution in these patients and treatment should be closely monitored (see sections 4.2 and 5.2).

Effects on Driving

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 performed. However, certain adverse reactions may affect the ability to drive and use machines (see section 4.8).