SIGNIFOR

Posology Acromegaly The recommended initial dose for the treatment of acromegaly is 40 mg of pasireotide every 4 weeks. The dose may be increased to a maximum of 60 mg for patients whose growth hormone (GH) and/or insulin-like growth factor-1 (IGF-1) levels are not fully controlled after 3 months of treatment with Signifor at 40 mg.

Management of suspected adverse reactions or over-response to treatment (IGF-1 < lower limit of normal) may require temporary dose reduction of Signifor. The dose may be decreased either temporarily or permanently. Cushing’s disease The recommended initial dose for the treatment of Cushing’s disease is 10 mg of pasireotide by deep intramuscular injection every 4 weeks.

The patient should be evaluated for clinical benefit after the first month of treatment and periodically thereafter. The dose may be titrated every 2 to 4 months based on response and tolerability. The maximum dose of Signifor in Cushing’s disease is 40 mg every 4 weeks.

If no clinical benefit is observed, the patient should be considered for discontinuation. Management of suspected adverse reactions or over-response to treatment (cortisol levels < lower limit of normal) may require dose reduction, interruption or discontinuation of Signifor.

Switch from subcutaneous to intramuscular formulation in Cushing’s disease There are no clinical data available on switching from the subcutaneous to the intramuscular pasireotide formulation. If such a switch should be required, the recommended initial dose for the treatment of Cushing’s disease is 10 mg of pasireotide by deep intramuscular injection every 4 weeks.

The patient should be monitored for response and tolerability and further dose adjustments may be needed. Missed dose If a dose of Signifor is missed the missed injection should be administered as soon as possible. The next dose should then be planned for 4 weeks after the injection is administered in order to resume the normal schedule of one dose every 4 weeks.

2). 2). Hepatic impairment Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). 2). 2). 4). Paediatric population The safety and efficacy of Signifor in children and adolescents aged 0 to 18 years have not been established.

No data are available. Method of administration Signifor is to be administered by deep intramuscular injection by a trained healthcare professional. Signifor suspension must only be prepared immediately before administration. The site of repeat intramuscular injections should be alternated between the left and right gluteal muscle.

6.

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 491patients who received pasireotide (419patients received pasireotide intramuscular use and 72 received pasireotide subcutaneous use) in phaseI, 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) Grade3 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 150patients who received pasireotide in the phaseIII study G2304 (median duration of exposure: 57weeks).

Patients were randomised in a 1:1 ratio to receive starting doses of either 10mg or 30mg pasireotide, with a possibility to up-titrate to a maximum dose of 40mg every 28days. The most common adverse reactions (incidence ≥1/10) in the phaseIII 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 30mg, but this was not consistent for all adverse reactions. Tabulated list of adverse reactions The adverse reactions in Table1 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). Table1 Adverse reactions by preferred term for pasireotide intramuscular use System Organ Class Very common Common Uncommon Not known Blood and lymphatic system disorders Anaemia Endocrine disorders Adrenal insufficiency* Metabolism and nutrition disorders Hyperglycaemia, diabetes mellitus Type2 diabetes mellitus, glucose tolerance impaired, decreased appetite Diabetic ketoacidosis Nervous system disorders Headache, dizziness Cardiac disorders Sinus bradycardia*, QT prolongation Gastrointestinal disorders Diarrhoea, nausea, abdominal pain* Abdominal distension, vomiting Steatorrhea Faeces discoloured Hepatobiliary disorders Cholelithiasis Cholecystitis*, cholestasis Skin and subcutaneous tissue disorders Alopecia, pruritus General disorders and administration site conditions Fatigue* Injection site reaction* Investigations Glycosylated haemoglobin increased, alanine aminotransferase increased, aspartate aminotransferase increased, gamma- glutamyltransferase increased, blood glucose increased, blood creatine phosphokinase increased, lipase increased Amylase increased, prothrombin time prolonged * Grouped terms: Adrenal insufficiency includes adrenal insufficiency and blood cortisol decreased.

Sinus bradycardia includes bradycardia and sinus bradycardia. Abdominal pain includes abdominal pain and abdominal pain upper. Injection site reaction includes injection site pain, injection site nodule, injection site discomfort, injection site bruising, injection site pruritus, injection site reaction, injection site hypersensitivity and injection site swelling.

Cholecystitis includes cholecystitis acute and cholecystitis chronic. Fatigue includes fatigue and asthenia. Description of selected adverse reactions Glucose metabolism disorders Acromegaly In acromegaly patients elevated fasting glucose level was the most frequently reported grade3/4laboratory abnormality in the two phaseIII studies.

6% and 0% of acromegaly patients treated with pasireotide intramuscular use and octreotide intramuscular use, respectively. 7% of acromegaly patients treated with pasireotide intramuscular use 40mg and 60mg respectively, and in no patients in the active control group.

Two cases of hyperglycaemiarelated emergencies (diabetic ketoacidosis and diabetic hyperglycaemic coma) were reported following a dose increase of pasireotide to 60mg in medical treatment naïve patients; one in a patient with untreated hyperglycaemia and HbA1c >8% prior to initiation of pasireotide and the other in a patient with untreated hyperglycaemia and a fasting plasma glucose of 359mg/dl, respectively.

In both studies, mean FPG and HbA1c levels peaked within the first three months of treatment with pasireotide intramuscular use. In medically naïve patients (study C2305), the mean absolute increase in FPG and HbA1c was similar at most of the time points for all patients treated with pasireotide intramuscular use irrespective of baseline values.

The degree and frequency of hyperglycaemia observed in the two pivotal studies in acromegaly patients were higher with Signifor intramuscular use than with active control (octreotide intramuscular use or lanreotide deep subcutaneous injection).

1% (CTC Grade3 and 4) for the active control. In the pivotal study with patients […]

Glucose metabolism Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients treated with pasireotide. 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. 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.

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.

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. 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.

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. 5). - with hypokalaemia and/or hypomagnesaemia. A baseline ECG is recommended prior to initiating therapy with Signifor.

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 and should be monitored periodically during therapy.

Hypocortisolism The suppression of ACTH (adrenocorticotropic hormone) secretion can result in hypocortisolism in patients treated with Signifor. g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia, hyponatraemia, […]

1. Severe hepatic impairment (Child Pugh C).