Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70 avenue du Général de Gaulle, 92800, Puteaux, France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe hepatic impairment (Child Pugh C).
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 A 1c [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 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.
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.
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.
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.
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.
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.
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 T 4 , GH/IGF-1) before and periodically during Signifor therapy should therefore be considered, as clinically appropriate.
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).
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).
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially ‘sodium-free’.
The influence of the P-gp inhibitor verapamil on the pharmacokinetics of subcutaneous pasireotide was tested in a drug-drug interaction study in healthy volunteers. No change in the pharmacokinetics (rate or extent of exposure) of pasireotide was observed.
Pasireotide may decrease the relative bioavailability of ciclosporin. Concomitant administration of pasireotide and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeutic levels.
Pasireotide should be used with caution in patients who are concomitantly receiving medicinal products that prolong the QT interval, such as class Ia antiarrhythmics (e.g. quinidine, procainamide, disopyramide), class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin), certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone), certain antihistamines (e.g. terfenadine, astemizole, mizolastine), antimalarials (e.g. chloroquine, halofantrine, lumefantrine), certain antifungals (ketoconazole, except in shampoo) (see also section 4.4).
Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patients receiving pasireotide concomitantly with bradycardic medicinal products, such as beta blockers (e.g. metoprolol, carteolol, propranolol, sotalol), acetylcholinesterase inhibitors (e.g. rivastigmine, physostigmine), certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil), certain antiarrhythmics (see also section 4.4).
Dose adjustments (decrease or increase) of insulin and antidiabetic medicinal products (e.g. metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly with pasireotide (see also section 4.4).
There is a limited amount of data from the use of pasireotide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Pasireotide is not recommended for use during pregnancy and in women of childbearing potential who are not using contraception (see section 4.4).
It is unknown whether pasireotide is excreted in human milk. Available data in rats have shown excretion of pasireotide in milk (see section 5.3). Breast-feeding should be discontinued during treatment with Signifor.
Studies in rats have shown effects on female reproductive parameters (see section 5.3). The clinical relevance of these effects in humans is unknown.
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.
A total of 201 Cushing’s disease patients received Signifor in phase II and III studies. The safety profile of Signifor was consistent with the somatostatin analogue class, except for the occurrence of hypocortisolism and degree of hyperglycaemia.
The data described below reflect exposure of 162 Cushing’s disease patients to Signifor in the phase III study. At study entry patients were randomised to receive twice-daily doses of either 0.6 mg or 0.9 mg Signifor. The mean age of patients was approximately 40 years and the majority of patients (77.8%) were female. Most (83.3%) patients had persistent or recurrent Cushing’s disease and few (≤5%) in either treatment group had received previous pituitary irradiation. The median exposure to the treatment up to the cut-off date of the primary efficacy and safety analysis was 10.37 months (0.03-37.8), with 66.0% of patients having at least six months' exposure.
Grade 1 and 2 adverse reactions were reported in 57.4% of patients. Grade 3 adverse reactions were observed in 35.8% of patients and Grade 4 adverse reactions in 2.5% of patients. Grade 3 and 4 adverse reactions were mostly related to hyperglycaemia. The most common adverse reactions (incidence ≥10%) were diarrhoea, nausea, abdominal pain, cholelithiasis, injection site reactions, hyperglycaemia, diabetes mellitus, fatigue and glycosylated haemoglobin increased.
Adverse reactions reported up to the cut-off date of the analysis are presented in Table 1. Adverse reactions are listed according to MedDRA primary system organ class. Within each system organ class, adverse reactions are ranked by frequency. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequencies were defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); not known (cannot be estimated from the available data).
Table 1. Adverse reactions in the phase III study and from post-marketing experience in Cushing’s disease patients:
Uncommon: Anaemia
Common: Adrenal insufficiency
Very common: Hyperglycaemia, diabetes mellitus
Common: Decreased appetite, type 2 diabetes mellitus, glucose tolerance impaired
Not known: Diabetic ketoacidosis
Common: Headache, dizziness
Common: Sinus bradycardia, QT prolongation
Common: Hypotension
Very common: Diarrhoea, abdominal pain, nausea
Common: Vomiting, abdominal pain upper
Very common: Cholelithiasis
Common: Cholecystitis*, cholestasis
Common: Alopecia, pruritus
Common: Myalgia, arthralgia
Very common: Injection site reaction, fatigue
Very common: Glycosylated haemoglobin increased
Common: Gamma glutamyltransfera se increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, blood glucose increased, blood amylase increased, prothrombin time prolonged
* Cholecystitis includes cholecystitis acute
Elevated glucose was the most frequently reported Grade 3 laboratory abnormality (23.2% of patients) in the phase III study in Cushing’s disease patients. Mean HbA1c increases were less pronounced in patients with normal glycaemia (n=62 overall) at study entry (i.e. 5.29% and 5.22% at baseline and 6.50% and 6.75% at month 6 for the 0.6 and 0.9 mg twice daily dose groups, respectively) relative to pre-diabetic patients (i.e. n=38 overall; 5.77% and 5.71% at baseline and 7.45% and 7.13% at month 6) or diabetic patients (i.e. n=54 overall; 6.50% and 6.42% at baseline and 7.95% and 8.30% at month 6). Mean fasting plasma glucose levels commonly increased within the first month of treatment, with decreases and stabilisation observed in subsequent months. Fasting plasma glucose and HbA1c values generally decreased over the 28 days following pasireotide discontinuation but remained above baseline values. Long-term follow-up data are not available. Patients with baseline HbA1c ≥7% or who were taking antidiabetic medicinal products prior to randomisation tended to have higher mean changes in fasting plasma glucose and HbA1c relative to other patients. Adverse reactions of hyperglycaemia and diabetes mellitus led to study discontinuation in 5 (3.1%) and 4 (2.5%) patients, respectively. One case of ketosis and one case of ketoacidosis have been reported during compassionate use of Signifor.
Monitoring of blood glucose levels in patients treated with Signifor is recommended (see section 4.4).
Gastrointestinal disorders were frequently reported with Signifor. These reactions were usually of low grade, required no intervention and improved with continued treatment.
Injection site reactions were reported in 13.6% of patients enrolled in the phase III study in Cushing’s disease. Injection site reactions were also reported in clinical studies in other populations. The reactions were most frequently reported as local pain, erythema, haematoma, haemorrhage and pruritus. These reactions resolved spontaneously and required no intervention.
Transient elevations in liver enzymes have been reported with the use of somatostatin analogues and were also observed in patients receiving pasireotide in clinical studies. The elevations were mostly asymptomatic, of low grade and reversible with continued treatment. Rare cases of concurrent elevations in ALT greater than 3 x ULN and bilirubin greater than 2 x ULN have been observed. All cases of concurrent elevations were identified within ten days of initiation of treatment with Signifor. The patients recovered without clinical sequelae and liver function test results returned to baseline values after discontinuation of treatment.
Monitoring of liver enzymes is recommended before and during treatment with Signifor (see section 4.4), as clinically appropriate.
Asymptomatic elevations in lipase and amylase were observed in patients receiving pasireotide in clinical studies. The elevations were mostly low grade and reversible while continuing treatment. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogues due to the association between cholelithiasis and acute pancreatitis.
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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