Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Glucose metabolism

Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients treated with pasireotide. Hyperglycaemia and, less frequently, hypoglycaemia, were observed in subjects participating in clinical studies with pasireotide (see section 4.8).

The degree of hyperglycaemia appeared to be higher in patients with pre-diabetic conditions or established diabetes mellitus. During the pivotal study, HbA1c levels increased significantly and stabilised but did not return to baseline values (see section 4.8). More cases of discontinuation and a higher reporting rate of severe adverse events due to hyperglycaemia were reported in patients treated with the dose of 0.9 mg twice daily.

The development of hyperglycaemia appears to be related to decreases in secretion of insulin (particularly in the post-dose period) and of incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]).

Glycaemic status (fasting plasma glucose/haemoglobin A1c [FPG/HbA1c]) should be assessed prior to -2-
starting treatment with pasireotide. FPG/HbA1c monitoring during treatment should follow established guidelines. Self monitoring of blood glucose and/or FPG assessments should be done weekly for the first two to three months and periodically thereafter, as clinically appropriate, as well as over the first two to four weeks after any dose increase. In addition, monitoring of FPG 4 weeks and HbA1c 3 months after the end of the treatment should be performed.

If hyperglycaemia develops in a patient being treated with Signifor, the initiation or adjustment of antidiabetic treatment is recommended, following the established treatment guidelines for the management of hyperglycaemia. If uncontrolled hyperglycaemia persists despite appropriate medical management, the dose of Signifor should be reduced or Signifor treatment discontinued (see also section 4.5).

There have been post-marketing cases of ketoacidosis with Signifor in patients with and without a history of diabetes. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history.
In patients with poor glycaemic control (as defined by HbA1c values >8% while receiving anti-diabetic therapy), diabetes management and monitoring should be intensified prior to initiation and during pasireotide therapy.

Liver tests

Mild transient elevations in aminotransferases are commonly observed in patients treated with pasireotide. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN have also been observed (see section 4.8). Monitoring of liver function is recommended prior to treatment with pasireotide and after one, two, four, eight and twelve weeks during treatment. Thereafter liver function should be monitored as clinically indicated.

Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding. If the finding is confirmed, the patient should be followed with frequent liver function monitoring until values return to pre-treatment levels. Therapy with pasireotide should be discontinued if the patient develops jaundice or other signs suggestive of clinically significant liver dysfunction, in the event of a sustained increase in AST (aspartate aminotransferase) or ALT of 5 x ULN or greater, or if ALT or AST elevations greater than 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN. Following discontinuation of treatment with pasireotide, patients should be monitored until resolution. Treatment should not be restarted.

Cardiovascular related events

Bradycardia has been reported with the use of pasireotide (see section 4.8). Careful monitoring is recommended in patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or medicinal products to control electrolyte balance, may be necessary (see also section 4.5).

Pasireotide has been shown to prolong the QT interval on the ECG in two dedicated healthy volunteer studies. The clinical significance of this prolongation is unknown.

In clinical studies in Cushing’s disease patients, QTcF of >500 msec was observed in two out of 201 patients. These episodes were sporadic and of single occurrence with no clinical consequence observed. Episodes of torsade de pointes were not observed either in those studies or in clinical studies in other patient populations.

Pasireotide should be used with caution and the benefit risk carefully weighed in patients who are at significant risk of developing prolongation of QT, such as those:
-      with congenital long QT syndrome.
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-     with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia.
-     taking antiarrhythmic medicinal products or other substances that are known to lead to QT prolongation (see section 4.5).
-     with hypokalaemia and/or hypomagnesaemia.

Monitoring for an effect on the QTc interval is advisable and ECG should be performed prior to the start of Signifor therapy, one week after the beginning of the treatment and as clinically indicated thereafter.
Hypokalaemia and/or hypomagnesaemia must be corrected prior to administration of Signifor and should be monitored periodically during therapy.

Hypocortisolism

Treatment with Signifor leads to rapid suppression of ACTH (adrenocorticotropic hormone) secretion in Cushing’s disease patients. Rapid, complete or near-complete suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially to transient hypocortisolism/hypoadrenalism.

It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia, hyponatraemia, hypoglycaemia). In the event of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of Signifor therapy may be necessary.

Gallbladder and related events

Cholelithiasis (gallstones) is a recognised adverse reaction associated with long-term use of somatostatin analogues and has frequently been reported in clinical studies with pasireotide (see section 4.8). There have been post-marketing cases of cholangitis in patients taking Signifor, which in the majority of cases was reported as a complication of gallstones. Ultrasonic examination of the gallbladder before and at 6 to 12 month intervals during Signifor therapy is therefore recommended. The presence of gallstones in Signifor-treated patients is largely asymptomatic; symptomatic stones should be managed according to clinical practice.

Pituitary hormones

As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary hormones other than ACTH cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4, GH/IGF-1) before and periodically during Signifor therapy should therefore be considered, as clinically appropriate.

Effect on female fertility

The therapeutic benefits of a reduction or normalisation of serum cortisol levels in female patients with Cushing’s disease could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with Signifor (see section 4.6).

Renal impairment

Due to the increase in unbound drug exposure, Signifor should be used with caution in patients with severe renal impairment or end stage renal disease (see section 5.2).

Sodium content

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially ‘sodium- free’.

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Effects on Driving

4.7   Effects on ability to drive and use machines

Signifor may have a minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue, dizziness or headache during treatment with Signifor.