Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
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.

Tabulated list of adverse reactions

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).



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Table 1      Adverse reactions in the phase III study and from post-marketing experience in Cushing’s disease patients
System Organ Class             Very common                Common             Uncommon       Not known Blood and lymphatic                                                         Anaemia system disorders
Endocrine disorders                                Adrenal insufficiency Metabolism and            Hyperglycaemia,          Decreased appetite,                      Diabetic nutrition disorders       diabetes mellitus        type 2 diabetes mellitus                 ketoacidosis glucose tolerance impaired
Nervous system                                     Headache, dizziness disorders
Cardiac disorders                                  Sinus bradycardia, QT prolongation
Vascular disorders                                 Hypotension
Gastrointestinal          Diarrhoea, abdominal     Vomiting, abdominal disorders                 pain, nausea             pain upper
Hepatobiliary             Cholelithiasis           Cholecystitis *,
disorders                                          cholestasis
Skin and                                           Alopecia, pruritus subcutaneous tissue disorders
Musculoskeletal and                                Myalgia, arthralgia connective tissue disorders
General disorders and Injection site reaction,
administration site       fatigue conditions
Investigations            Glycosylated             Gamma haemoglobin increased glutamyltransferase increased, alanine aminotransferase increased, aspartate aminotransferase increased, lipase increased, blood glucose increased,
blood amylase increased, prothrombin time prolonged
*Cholecystitis includes cholecystitis acute

Description of selected adverse reactions

Glucose metabolism disorders
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 -7-
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
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
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.

Liver enzymes
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.

Pancreatic enzymes
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 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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il