Signifor

HOS-155113 · has-adverse-reaction-information · PDF-Seite 7

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). 7 Table 1 Adverse reactions in the phase III study and from post-marketing experience in Cushing’s disease patients System Organ Very common Common Uncommon Not known Class Blood and Anaemia lymphatic system disorders Endocrine Adrenal disorders insufficiency Metabolism and Hyperglycaemi

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HOS-155119 · has-adverse-reaction-information · PDF-Seite 22

Summary of the safety profile The safety profile of pasireotide intramuscular use is consistent with the somatostatin analogue class, except for the higher degree and frequency of hyperglycaemia seen with pasireotide intramuscular use. The safety profile of pasireotide intramuscular use was largely similar between the acromegaly and Cushing’s disease indications. Acromegaly In acromegaly, the safety assessment was made based on 491 patients who received pasireotide (419 patients received pasireotide intramuscular use and 72 received pasireotide subcutaneous use) in phase I, II and III studies. The most common adverse reactions (incidence ≥1/10) from the pooled safety data from the phase III studies C2305 and C2402 were (in decreasing order): diarrhoea (most common in study C2305), cholelithiasis, hyperglycaemia (most common in study C2402) and diabetes mellitus. Common Toxicity Criteria (CTC) Grade 3 and 4 adverse reactions were mostly related to hyperglycaemia. Cushing’s disease In Cushing’s disease, the safety assessment of the intramuscular formulation was made based on 150 patients who received pasireotide in the phase III study G2304 (median duration of exposure: 57 weeks). Patients were randomised in a 1:1 ratio to receive starting doses of either 10 mg or 30 mg pasireotide, with a possibility to up-titrate to a maximum dose of 40 mg every 28 days. The most common adverse reactions (incidence ≥1/10) in the phase III study G2304 were hyperglycaemia, diarrhoea, cholelithiasis and diabetes mellitus. The frequency and severity of adverse reactions tended to be higher with the higher starting dose of 30 mg, but this was not consistent for all adverse reactions. Tabulated list of adverse reactions The adverse reactions in Table 1 include events reported in the pivotal studies with the intramuscular formulation in patients with acromegaly and with Cushing’s disease. 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). 22 Table 1 Adverse reactions by preferred term for pasireotide intramuscular use System Organ Very

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HOS-155109 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe hepatic impairment (Child Pugh C).

HOS-155115 · has-contraindication-information · PDF-Seite 18

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe hepatic impairment (Child Pugh C).

HOS-155114 · has-indication-information · PDF-Seite 16

Treatment of adult patients with acromegaly for whom surgery is not an option or has not been curative and who are inadequately controlled on treatment with another somatostatin analogue. Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed. The 60 mg strength is only to be used in the treatment of acromegaly.

HOS-155108 · has-indication-information · PDF-Seite 2

Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed.

HOS-155111 · has-interaction-information · PDF-Seite 6

Anticipated pharmacokinetic interactions resulting in effects on pasireotide 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. Anticipated pharmacokinetic interactions resulting in effects on other medicinal products 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. Anticipated pharmacodynamic interactions Medicinal products that prolong the QT interval 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). Bradycardic medicinal products 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). Insulin and antidiabetic medicinal products 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).

HOS-155117 · has-interaction-information · PDF-Seite 20

Anticipated pharmacokinetic interactions resulting in effects on pasireotide 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. 20 Anticipated pharmacokinetic interactions resulting in effects on other medicinal products 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. Anticipated pharmacodynamic interactions Medicinal products that prolong the QT interval 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). Bradycardic medicinal products 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). Insulin and antidiabetic medicinal products 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).

HOS-155118 · has-pregnancy-information · PDF-Seite 21

Pregnancy There is a limited amount of data from the use of pasireotide in pregnant women. Studies in animals in which pasireotide was administered via the subcutaneous route 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). Breast-feeding It is unknown whether pasireotide is excreted in human milk. Available data in rats in which pasireotide was administered via the subcutaneous route have shown excretion of pasireotide in milk (see section 5.3). Breast-feeding should be discontinued during treatment with Signifor. Fertility Studies in rats in which pasireotide was administered via the subcutaneous route have shown effects on female reproductive parameters (see section 5.3). The clinical relevance of these effects in humans is unknown.

HOS-155112 · has-pregnancy-information · PDF-Seite 6

Pregnancy 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). Breast-feeding 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. 6 Fertility Studies in rats have shown effects on female reproductive parameters (see section 5.3). The clinical relevance of these effects in humans is unknown.

HOS-155110 · has-warning-information · PDF-Seite 3

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 3 (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 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

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HOS-155116 · has-warning-information · PDF-Seite 18

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, 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. 18 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

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