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).

In patients who developed hyperglycaemia, the condition generally appeared to respond to antidiabetic therapy. Dose reductions or discontinuation of treatment with pasireotide due to hyperglycaemia were infrequent in clinical studies with pasireotide.

The development of hyperglycaemia appears to be related to decreases in secretion of insulin 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 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 three months and periodically thereafter, as clinically appropriate, as well as over the first four to six 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 LAR, 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 LAR should be reduced or Signifor LAR treatment discontinued (see also section 4.5).

There have been post-marketing cases of ketoacidosis with Signifor LAR 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 intramuscular use and after the first two to three weeks, then monthly for three months on treatment. Thereafter liver function should be monitored as clinically indicated.

Patients who develop increased transaminase levels should be monitored frequently 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 if the liver function abnormalities are suspected to be related to pasireotide.

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 performed with the subcutaneous formulation. The clinical significance of this prolongation is unknown. The phase III clinical studies in acromegaly patients did not identify any clinically meaningful differences in the QT prolongation events between pasireotide intramuscular use and the somatostatin analogues which were tested as active comparator. All QT-related events were transient and resolved without therapeutic intervention.

Episodes of torsade de pointes were not observed in any clinical study with pasireotide.

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.
-      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.

A baseline ECG is recommended prior to initiating therapy with Signifor LAR. Monitoring for an effect on the QTc interval is advisable 21 days after the beginning of the treatment and as clinically indicated thereafter. Hypokalaemia and/or hypomagnesaemia must be corrected prior to administration of Signifor LAR and should be monitored periodically during therapy.

Hypocortisolism

The suppression of ACTH (adrenocorticotropic hormone) secretion can result in hypocortisolism in patients treated with Signifor LAR. 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 LAR therapy may be necessary. Rapid decreases in cortisol levels may be associated with decreases in white blood cell count.

Gallbladder and related events

Cholelithiasis (gallstones) is a recognised adverse reaction associated with 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 LAR, 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 LAR therapy is therefore recommended. The presence of gallstones in Signifor LAR-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 GH and/or IGF-1 in patients with acromegaly and ACTH/cortisol in patients with Cushing’s disease cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4) before and periodically during Signifor LAR therapy should therefore be considered, as clinically appropriate.

Effect on female fertility

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with Signifor LAR (see section 4.6).

Coagulation abnormalities

Patients with significantly increased prothrombin time (PT) and partial thromboplastin time (PTT) values or patients receiving coumarin-derivative or heparin-derivative anticoagulants were excluded from clinical studies with pasireotide as the safety of the combination with such anticoagulants has not been established. If concomitant use of coumarin-derivative or heparin-derivative anticoagulants with Signifor LAR intramuscular use cannot be avoided, patients should be monitored regularly for alterations in their coagulation parameters (PT and PTT) and the anticoagulant dose adjusted accordingly.

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’.

Effects on Driving

4.7    Effects on ability to drive and use machines

Signifor LAR 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 LAR.