Signifor LAR prescribing information: approved by Swissmedic 17 February 2015 Page 1 of 22

Transcription

1 Page 1 of 22 Signifor LAR Composition Active substance: Pasireotide (as pasireotide pamoate) Excipients Vial of active substance: Copoly (dl-lactide-glycolide) Pre-filled syringe of solvent: Mannitol, carmellose sodium, poloxamer 188, water for injections. Pharmaceutical form and quantity of active substance per unit Powder and solvent for suspension for injection Powder: Slightly yellowish to yellowish powder in vial. Solvent for suspension for injection: clear, colourless to slightly yellow or slightly brown solution in a pre-filled syringe Each vial contains: Signifor LAR 20 mg 20 mg pasireotide (as pamoate) Signifor LAR 40 mg 40 mg pasireotide (as pamoate) Signifor LAR 60 mg 60 mg pasireotide (as pamoate) Indications/Potential uses Signifor LAR is indicated for the treatment of patients with acromegaly in whom surgery or radiotherapy is inappropriate or ineffective, and/or other medical therapies have failed to achieve the desired therapeutic effect. Dosage/Administration General target population The recommended initial dose of Signifor LAR is 40 mg administered by deep intramuscular injection every 4 weeks (q28d).

2 Page 2 of 22 The dose may be increased to a maximum of 60 mg for patients whose GH and/or IGF-1 levels are not fully controlled after 3 months of treatment with Signifor LAR at 40 mg. Management of suspected adverse effects may require dose reduction of Signifor LAR. The dose may be decreased either temporarily or permanently by 20 mg decrements. Special patient populations Patients with renal impairment No dose adjustment is required in patients with impaired renal function. Patients with hepatic impairment Dose adjustment is not required in patients with mildly impaired hepatic function (Child-Pugh A). For patients with moderately impaired hepatic function (Child-Pugh B) the recommended initial dose is 20 mg every 4 weeks and the maximum recommended dose is 40 mg every 4 weeks (see Pharmacokinetics ). Signifor LAR should not be used in patients with severe hepatic impairment (Child-Pugh C) (see Contraindications ). Children and adolescents The efficacy and safety of use in children and adolescents have not been studied. Elderly patients There are limited data on the use of Signifor in patients older than 65 years. There is no evidence that dose adjustment is required in elderly patients. Administration Signifor LAR should only be administered by deep intramuscular injection by a trained healthcare professional. Signifor LAR suspension must only be prepared immediately before administration. The site of repeat intramuscular injections should be alternated between the left and right gluteal muscle (see Other information / Instructions for use and handling ).

3 Page 3 of 22 Contraindications Hypersensitivity to the active substance or any of the excipients. Severe hepatic impairment (Child-Pugh C). Warnings and precautions Glucose metabolism Changes in glucose regulation are likely during treatment with pasireotide. Hyperglycaemia, raised fasting plasma glucose, an increase in HbA1c and, less often, hypoglycaemia have been observed in clinical studies of pasireotide. In the two pivotal studies in acromegaly patients, the grade and frequency of hyperglycaemia-related adverse effects were higher with intramuscular pasireotide than with the active control. The development of hyperglycaemia correlates with decreased secretion of insulin and incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). The degree of glucose deregulation is higher in patients with pre-diabetic metabolic status or frank diabetes. For further information, see Adverse effects. Glycaemic status (fasting plasma glucose and HbA1c) should be assessed before starting treatment and regularly monitored during treatment. Selfmonitoring of blood glucose and fasting plasma glucose/hba1c levels should be done weekly for the first three months of treatment and periodically thereafter at clinically appropriate intervals, as well as weekly over the first four to six weeks after any dose increase. Fasting plasma glucose levels should be monitored for three weeks, and HbA1c levels for three months after the end of treatment. Acromegaly patients who developed hyperglycaemia generally appeared to respond to antidiabetic therapies. If hyperglycaemia occurs, prompt initiation or adjustment of hyperglycaemia therapy with incretins, insulin secretagogues and/or insulin is indicated. If hyperglycaemia cannot be controlled despite appropriate medical measures, the Signifor dose should be reduced or treatment discontinued. Patients with poor glycaemic control (defined as HbA1c values >8% on antidiabetic therapy) are at higher risk of developing severe hyperglycaemia and associated

4 Page 4 of 22 complications (e.g. ketoacidosis). In patients with poor glycaemic control, diabetes management and monitoring should be intensified before and during treatment. Cardiovascular events Bradycardia has been observed during treatment with pasireotide. Patients with cardiac disease and/or risk factors for bradycardia such as a history of clinically significant bradycardia, acute myocardial infarction or Mobitz type II block, congestive heart failure (NYHA class III or IV), unstable angina, ventricular tachycardia or ventricular fibrillation must be carefully monitored. It may be necessary to adjust the dose of drugs such as beta blockers, calcium channel blockers or agents to control electrolyte balance. Pasireotide was shown to prolong the QT interval in the ECG in two studies in healthy volunteers (see also Properties/Actions ). The phase III studies in acromegaly patients did not identify any clinically meaningful differences in QT prolongation events between Signifor LAR and the somatostatin analogues which were tested as active comparators. All QTrelated events were transient and resolved without therapeutic intervention. Episodes of torsade de pointes were not observed, either in these studies or in clinical studies in other patient populations. Pasireotide should be used with caution in patients at significant risk of QT interval prolongation, 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 anti-arrhythmic medicinal products or other substances that are known to lead to QT prolongation with hypokalaemia and/or hypomagnesaemia A baseline ECG is recommended prior to initiating therapy with Signifor LAR. Monitoring for a possible effect on the QTc interval is advisable 21 days after initiating therapy and whenever clinically indicated. Hypokalaemia or hypomagnesaemia must be corrected prior to Signifor LAR administration and should be monitored periodically during therapy.

5 Page 5 of 22 Liver function tests Mild transient elevations in aminotransferases are commonly observed in patients treated with pasireotide. A few cases of concurrent elevations in alanine aminotransferase (ALT) greater than 3 upper limit normal (ULN) and bilirubin greater than 2 ULN have also been observed (see Adverse effects ). Monitoring of liver function is recommended prior to treatment with Signifor LAR, and after the first 2 to 3 weeks, then monthly for 3 months on treatment. Thereafter, liver function should be monitored as clinically indicated. Patients with increased transaminase levels should undergo frequent liver function tests until values return to pre-treatment levels. Therapy with Signifor LAR should be discontinued if the patient develops jaundice or other signs of clinically significant liver impairment, in the event of a sustained increase in aspartate aminotransferase (AST) or ALT of 5 ULN or greater, or if ALT or AST elevation greater than 3 ULN occurs concurrently with bilirubin elevation greater than 2 ULN. Following discontinuation of treatment with Signifor LAR, patients should be monitored until resolution. Treatment should not be restarted if the liver function abnormalities are suspected to be related to Signifor LAR. Gallbladder and related events Gallstone formation is a known adverse effect of long-term treatment with somatostatin analogues and has been frequently observed in clinical studies of pasireotide (see Adverse effects ). Ultrasound examination of the gallbladder before, and at 6- to 12-month intervals during Signifor LAR therapy is therefore recommended. The occurrence of gallstones in Signifor LAR-treated patients is largely asymptomatic; symptomatic stones should be managed according to clinical practice. Pituitary hormones Deficiency of pituitary-secreted hormones is common after trans-sphenoidal surgery and even more frequently observed after pituitary radiotherapy. Patients with acromegaly may therefore present with deficiency of one or more pituitary hormones. As the pharmacological effect of pasireotide mimics that of somatostatin, inhibition of other pituitary hormones in addition to GH/IGF-1

6 Page 6 of 22 cannot be ruled out. Therefore, pituitary function (e.g. TSH/free T 4, ACTH) should be monitored prior to initiation of therapy with Signifor LAR and periodically during treatment as clinically indicated. Hypocortisolism Treatment with Signifor LAR can lead to suppression of adrenocorticotropic hormone (ACTH) secretion. Infrequent cases of hypocortisolism have been reported in clinical studies with pasireotide in acromegaly patients. It is therefore recommended to monitor and instruct patients on the signs and symptoms of hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatraemia or hypoglycaemia). In case of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of treatment with Signifor LAR may be necessary. Fertility The effect of pasireotide on human fertility is unknown. It should be borne in mind when treating women of childbearing potential that female fertility might be reduced (see Preclinical data ). On the other hand, treatment may achieve a reduction in growth hormone (GH) level and normalisation of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients, which could potentially restore fertility. Where indicated, female patients of childbearing potential should be advised to use adequate contraception during treatment with pasireotide (see Pregnancy/Breastfeeding ). Interactions Pasireotide is moderately protein-bound, metabolically stable and not a substrate, inhibitor or inducer of any major CYP450 enzymes. Pasireotide appears to be a substrate of the efflux transporter P-glycoprotein (P-gp), but is not an inhibitor or inducer of P-gp. Pasireotide is not a substrate of the efflux transporter breast cancer resistance protein (BCRP), nor of the influx transporters organic cation transporter 1 (OCT1), organic aniontransporting polypeptides (OATP) 1B1, 1B3 or 2B1. Pasireotide is not expected to inhibit uridine diphosphate glucuronosyltransferase 1A1

7 Page 7 of 22 (UGT1A1), influx transporter OAT1 or OAT3, OATP 1B1 or 1B3, OCT1 or OCT2, efflux transporter P-gp, BCRP, multi-drug resistance protein 2 (MRP2) or bile salt export pump (BSEP) at clinically relevant concentrations. Based on these in vitro data, the potential for protein binding, metabolism and/or transporter-mediated interactions is low between pasireotide and comedications in vivo. The influence of a P-gp inhibitor on the pharmacokinetics of pasireotide administered as Signifor s.c. injection has been tested in a drug-drug interaction study with co-administration of verapamil in healthy volunteers. No change in the rate or extent of pasireotide availability was observed. Caution is required when co-administering Signifor with anti-arrhythmic medicines or drugs that may prolong the QT interval (see Warnings and precautions ). Anticipated interactions affecting other drugs Limited published data suggest that somatostatin analogues might indirectly reduce metabolic clearance of compounds metabolised by CYP450 enzymes by suppressing growth hormone secretion. Available data cannot exclude the possibility that pasireotide may exert such an indirect effect. Caution is required when administering pasireotide concomitantly with drugs that have a low therapeutic index and are metabolised mainly by CYP3A4. In dogs, pasireotide has been found to decrease the blood level of ciclosporin by reducing its intestinal absorption. It is unknown whether such interaction occurs in humans. Ciclosporin dose adjustment may therefore be necessary when co-administering pasireotide and ciclosporin. Co-administration of bromocriptine with somatostatin analogues may increase the availability of bromocriptine. The possibility cannot be excluded that pasireotide may exert such an effect. Pregnancy/Breastfeeding Pregnancy There are no adequate and well-controlled studies in pregnant women. Studies in animals with s.c. administration have shown reproductive toxicity (see

8 Page 8 of 22 Preclinical data ). As the potential risk to humans is unknown, Signifor LAR should not be administered to pregnant women unless clearly necessary. Breastfeeding It is not known whether pasireotide is excreted in human milk. Studies in rats with pasireotide via the s.c. route have shown excretion of pasireotide in milk. As a risk to the breastfed child cannot be excluded, Signifor LAR should not be administered to nursing mothers. Effects on ability to drive and use machines Pasireotide has no effect on the ability to drive or use machines. Adverse effects Safety assessment was based on 491 acromegaly patients who received pasireotide (419 patients received Signifor LAR and 72 received Signifor s.c.) in phase I, II and III studies. The safety profile of Signifor LAR is consistent with the somatostatin analogue class, except for the higher degree and frequency of hyperglycaemia seen with Signifor LAR. The efficacy and safety of Signifor LAR in patients with active acromegaly was evaluated in two blinded, active-controlled studies. In the study in patients who had not been previously treated with drugs and who had failed or were unsuitable for surgery, the most frequent adverse effects reported in the Signifor LAR and Sandostatin LAR arms in the core and extension phase were diarrhoea (33.1% and 40.6%), cholelithiasis (30.9% and 36.7%), hyperglycaemia (28.1% and 7.2%) and diabetes mellitus (19.7% and 3.9%). Common Toxicity Criteria (CTC) grade 3 or 4 adverse effects reported for more than 2% of the patients in the Signifor LAR or Sandostatin LAR arm were diabetes mellitus (4.5% and 0%), diarrhoea (0.6% and 2.8%) and hyperglycaemia (2.2% and 0.6%). In the study in patients who did not achieve biochemical control (GH 2.5 micrograms/litre and normalised IGF-1) on therapy with first-generation somatostatin analogues (SSAs) (referred to as inadequately controlled patients ), the most frequent adverse effects observed with Signifor LAR 40 mg, 60 mg and active control in the 24-week core phase of study C2402

9 Page 9 of 22 were hyperglycaemia (33.3%, 29.0% and 6.1%), diabetes mellitus (19.0%, 25.8% and 4.5%) and diarrhoea (11.1%, 19.4 and 1.5%). CTC grade 3 or 4 adverse effects reported for more than 2% of the patients in the Signifor LAR 40 mg, 60 mg or active control group were hyperglycaemia (11.1%, 8.1% and 0%), diabetes mellitus (0%, 3.2% and 0%) and abdominal pain (1.6%, 0%, 0%). The following adverse effects were reported in clinical studies of pasireotide, and are listed below according to MedDRA terminology. Frequencies were defined as follows: very common ( 1/10), common ( 1/100 to <1/10), uncommon ( 1/1000 to <1/100). Blood and lymphatic system disorders Common: Anaemia. Endocrine disorders Common: Adrenal insufficiency, blood cortisol decreased. Metabolism and nutrition disorders Very common: Hyperglycaemia, diabetes mellitus. Common: Type 2 diabetes mellitus, impaired glucose tolerance. Nervous system disorders Common: Dizziness, headache. Cardiac disorders Common: Sinus bradycardia; QT prolongation. Gastrointestinal disorders Very common: Diarrhoea, abdominal pain. Common: Abdominal distension, nausea. Hepatobiliary disorders Very common: Cholelithiasis. Common: ALT increased, blood amylase increased. Skin and subcutaneous tissue disorders Very common: Alopecia.

10 Page 10 of 22 General disorders and administration site reactions Common: Injection site reactions (injection site pain, induration, discomfort, haematoma, pruritus, swelling). Investigations Common: Blood creatine phosphokinase increased, blood glucose increased, glycosylated haemoglobin increased. Description of selected adverse effects Glucose metabolism disorders In the first study, mean fasting blood glucose/haemoglobin A1c (FPG and HbA1c) levels peaked within the first 3 months of treatment with Signifor LAR. The mean absolute increase in FPG and HbA1c was similar for all patients treated with Signifor LAR, irrespective of baseline values. Grade 3 elevated fasting glucose levels were reported in 9.7% and 0.6%, and grade 4 in 0.6% and 0% of patients treated with Signifor LAR and the control, respectively. Diabetes mellitus and hyperglycaemia led to study discontinuation in 3 (1.7%) vs. 2 (1.1%) patients and in 2 (1.1%) vs. 0 patients in the Signifor LAR and control arms, respectively. In the second study in inadequately controlled patients, CTC grade 3 elevated fasting glucose levels were reported in 14.3% and 17.7% of patients in the Signifor LAR 40 mg and 60 mg group, respectively, and none in the active control group. Hyperglycaemia-related adverse effects led to study discontinuation in 6 patients (4.6%) in the Signifor LAR arm only (2 patients [1.5%] in the 40 mg group and 4 patients [3.1%] in the 60 mg group). The elevations of fasting plasma glucose and HbA1c observed with Signifor LAR treatment are reversible after discontinuation, as shown by the rapid decrease in FPG and HbA1c levels in patients who crossed from Signifor LAR to Sandostatin LAR in the extension of study C2305. In study C2402, CTC grade 3 elevated fasting glucose levels were reported in 14.3% and 17.7% of patients in the Signifor LAR 40 mg and 60 mg group, respectively, and none in the active control group. Hyperglycaemia-related adverse effects led to study discontinuation in 6 patients (4.6%) in the Signifor

11 Page 11 of 22 LAR arm only (2 patients [1.5%] in the 40 mg group and 4 patients [3.1%] in the 60 mg group). Monitoring of blood glucose levels is recommended in patients treated with Signifor LAR (see Warnings and precautions ). Gastrointestinal disorders Gastrointestinal disorders were frequently reported with the use of Signifor LAR. These events were usually of low grade, required no intervention and improved with continued treatment. Gastrointestinal disorders were less frequent in inadequately controlled patients as compared to treatment-naïve patients. Overdose In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient s clinical status, until resolution of the symptoms. Properties/Actions ATC code: H01CB05 Mechanism of action Pasireotide (cyclohexapeptide) is a somatostatin analogue that binds with high affinity to human somatostatin receptor subtypes SSTR 1, 2, 3 and 5. Pharmacodynamic properties Somatostatin receptors are expressed in many tissues, especially in neuroendocrine tumours in which hormones are excessively secreted, including growth hormone in acromegaly. Due to its broad binding profile to somatostatin receptors, pasireotide has the potential to stimulate both SSTR2 and SSTR5 receptor subtypes relevant to inhibition of GH and IGF-1 secretion. It is therefore potentially more effective in the treatment of acromegaly patients than other somatostatin analogues. In rat primary GH-secreting pituitary cells in vitro, pasireotide was 3 times more potent than octreotide in reducing GHRH-induced GH secretion. In vivo studies showed a strong inhibitory effect of pasireotide on GH and IGF-1. In addition, the inhibitory effect of octreotide

12 Page 12 of 22 on IGF-1 in vivo was transient, whereas the inhibitory effect of pasireotide on IGF-1 showed less tachyphylaxis. Glucose metabolism The development of hyperglycaemia after s.c. pasireotide administration was correlated to a significant decrease in insulin secretion and incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). Pasireotide did not affect insulin sensitivity. Incretin-based therapy (GLP-1 agonists and DDP-IV inhibitors) was most efficacious in treating pasireotide-associated hyperglycaemia in healthy volunteers. Cardiac electrophysiology The effect of Signifor on the QT interval was assessed in two QT studies. In both studies an effect of pasireotide on the QT interval was observed. One of the studies, with a dose of 1950 µg twice daily, measured a maximum mean placebo-adjusted QTcF value of 17.5 ms (90% confidence interval [CI]: 15.53; 19.38). The other study found mean placebo-adjusted QTcI values of ms (90% CI: 11.38; 15.01) and ms (90% CI: 14.30; ms), respectively, at the doses of 600 µg and 1950 µg twice daily. At both doses there was a reduction in heart rate, with a maximum difference from placebo observed after 1 hour for pasireotide 600 µg twice daily ( bpm) and after 30 minutes for pasireotide 1950 µg twice daily ( bpm). The predicted peak concentrations for the maximum Signifor LAR dose of 60 mg in acromegaly patients with normal liver function and of 40 mg in acromegaly patients with moderate hepatic impairment of 25.8 ng/ml and 28.8 ng/ml, respectively, are similar to the peak concentration observed on Signifor 600 micrograms s.c. twice daily (24.3 ng/ml) and below the peak concentration observed on 1950 micrograms twice daily (80.6 ng/ml). The increase in QT interval with administration of pasireotide is not mediated by an effect on the herg potassium channel. Cardiac restitution, the ability of the heart to recover from each preceding beat, was measured in a continuous 24-hour ECG to determine the effect of pasireotide on arrhythmia vulnerability. Pasireotide significantly improved all restitution parameters in the presence of QT prolongation, indicating that pasireotide-mediated QT prolongation may not be associated with an increased pro-arrhythmic risk.

13 Page 13 of 22 Further, quantitative T wave morphological analysis showed no changes indicative of impaired spatial heterogeneity of cardiac repolarisation during pasireotide treatment. Clinical efficacy The efficacy and safety of Signifor LAR in patients with active acromegaly was evaluated in two blinded, active-controlled studies. The primary efficacy endpoint was to compare the proportion of patients achieving biochemical control (defined as mean GH levels <2.5 micrograms/litre and normalisation of sex- and age-adjusted IGF-1). One study enrolled 358 patients who had either undergone adenectomy or were not eligible for surgery (contraindication, non-consent to surgery). The primary efficacy endpoint was assessed at 12 months. The percentage of patients achieving biochemical control was 31.3% and 19.2% for intramuscular pasireotide and octreotide LAR, respectively (p-value = 0.007). Biochemical control was achieved early in the study in both arms (i.e. month 3). The proportion of patients with a reduction of tumour volume greater than 20% at month 12 was 80.8% for intramuscular pasireotide and 77.4% for octreotide LAR. Quality of life assessments at month 12 showed statistically significant improvements in the physical, psychological and global AcroQoL scores for both Signifor LAR and octreotide compared to baseline. During the extension phase, 74 patients continued treatment with intramuscular pasireotide and 46 patients continued with octreotide LAR. At month 25, 48.6% of patients (36/74) in the intramuscular pasireotide group and 45.7% (21/46) in the octreotide LAR group achieved biochemical control. The percentage of patients achieving a mean GH <2.5 micrograms/litre and normalisation of IGF-1 at the same time point was similar in both treatment arms. During the extension phase, tumour volume continued to decrease and improvements in acromegaly signs and symptoms remained comparable between the two treatments arms. AcroQoL scores remained numerically higher in the intramuscular pasireotide arm than in the octreotide LAR arm throughout the extension phase. In a study of previously treated, inadequately controlled acromegaly patients (defined as patients with a mean GH concentration of a 5-point profile over a 2-hour period >2.5 micrograms/litre and sex- and age-adjusted IGF-1 >1.3

14 Page 14 of 22 upper limit of normal (ULN); patients had to have been treated with the maximum indicated dose of Sandostatin LAR (30 mg) or lanreotide ATG (120 mg) for at least 6 months prior to randomisation), either pasireotide 40 mg (n=65) or 60 mg (n=65) or the previous medication (n=68) was administered. Two-thirds of patients had undergone surgery. Baseline mean GH was 17.6 micrograms/litre, 12.1 micrograms/litre and 9.5 micrograms/litre in the 40 mg, 60 mg and active control groups, respectively. IGF-1 mean values at baseline were 2.6, 2.8 and 2.9 ULN, respectively. The proportion of patients achieving biochemical control at week 24 was 15.4% (p-value = 0.006) and 20.0% (p-value <0.0001) for intramuscular pasireotide 40 mg and 60 mg, respectively, compared to 0% in the active control arm (octreotide LAR, lanreotide ATG). The proportion of patients with a reduction or no change in pituitary tumour volume at week 24 was 81.0% and 70.3% on intramuscular pasireotide 40 mg and 60 mg, respectively, and 50.0% in the active control group. Furthermore, a higher proportion of patients on intramuscular pasireotide (18.5% and 10.8% for 40 mg and 60 mg, respectively) than active comparator (1.5%) achieved a reduction in tumour volume of at least 25%. At week 24, improvements in physical, psychological and global AcroQoL scores were observed in both the 40 mg and 60 mg intramuscular pasireotide groups. In the 40 mg intramuscular pasireotide treatment group, these changes were statistically significant for the AcroQoL physical subscore. In the 60 mg intramuscular pasireotide group, these changes were statistically significant for both the physical and psychological subscores and the global score. There were no statistically significant changes in the octreotide LAR or lanreotide ATG group. The mean improvement from baseline was greatest in the 60 mg intramuscular pasireotide group for all scores. However, the differences in changes from baseline to week 24 between the treatment groups were not statistically significant. Pharmacokinetics Absorption The relative bioavailability of pasireotide administered as Signifor LAR over s.c. Signifor administration is complete. Steady state for pasireotide

15 Page 15 of 22 administered as Signifor LAR is achieved after three months. Following multiple i.m. doses every 4 weeks (q28d), Signifor LAR demonstrates approximately dose-proportional pharmacokinetic exposures in the dose range of 20 mg to 60 mg every 4 weeks. Distribution Pasireotide has a volume of distribution (V z /F) of >100 litres. Pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration. Pasireotide is likely to be a substrate of P-gp; it has not been studied for ability to penetrate the cerebrospinal fluid. Metabolism Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. Clearance is litres/hour. Elimination half-life t ½ is approximately 16 days. Elimination Pasireotide is eliminated intact mainly via hepatic clearance (biliary excretion) and only to a small extent by the kidney ± 6.63% of radiolabelled pasireotide was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in faeces and 7.63 ± 2.03% in urine. Special patient populations Elderly patients Data on patients with acromegaly older than 65 years are limited but do not suggest any clinically significant differences in safety and efficacy compared to younger patients. Children and adolescents No studies have been performed in children and adolescents. Patients with renal impairment Clinical studies have not been performed in patients with impaired renal function.

16 Page 16 of 22 Patients with hepatic impairment In subjects with hepatic impairment given a single dose of Signifor s.c., those with moderate to severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than patients with normal hepatic function. AUC inf was increased by 60% and 79%, C max increased by 67% and 69%, and CL/F decreased by 37% and 44%, respectively, in the moderate and severe hepatic impairment groups relative to the control group. Demographics Population pharmacokinetic analyses of pasireotide administered as Signifor LAR suggest that ethnicity, gender and body weight do not have a clinically relevant influence on pharmacokinetic parameters. No dose adjustment is required for demographics. Preclinical data Non-clinical safety studies conducted with pasireotide as s.c. injection included safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenicity, and reproductive and developmental toxicity. Additionally, tolerability and repeated-dose toxicity studies were conducted with pasireotide LAR via the i.m. route. Most findings in the repeated toxicity studies were reversible and attributable to the pharmacology of pasireotide. The effects in the preclinical studies were observed at exposures similar to or greater than the maximum exposure to human therapeutic doses. In safety pharmacology studies (with pasireotide as s.c. injection), pasireotide had no adverse effects on respiratory or cardiovascular functions. Decreases in general and behavioural activity were observed in mice at a dose of 12 mg/kg, equivalent to approximately 27-fold the estimated maximum daily dose for pasireotide LAR, based on body surface area. Pasireotide was found non-genotoxic in two in vitro genotoxicity tests (Ames test and chromosome aberration test in human peripheral lymphocytes). Pasireotide was not genotoxic in an in vivo rat bone marrow micronucleus test at doses up to 50 mg/kg, corresponding to a dose almost 224-fold higher than the estimated maximum daily dose of pasireotide LAR, based on body surface area.

17 Page 17 of 22 Carcinogenicity studies in rats and transgenic mice did not identify any carcinogenic potential. In embryo-fetal development studies in rats and rabbits with pasireotide as s.c. injection, pasireotide was not teratogenic at maternally toxic doses (equivalent to 10 [rat] and 5 [rabbit] mg/kg/day) leading to exposures (AUC 0-24h ) equivalent, respectively, to 106- and 30-fold that at the MRHD of pasireotide LAR. At 10 mg/kg/day in rats, the frequency of early/total resorptions and malrotated limbs was increased. At 5 mg/kg/day in rabbits, increased abortions, reduced fetal weights and ensuing skeletal variations were observed. Reduced fetal weight and ensuing delayed ossification were seen at 1 mg/kg/day (4.8- fold higher exposure than at the MRHD for pasireotide LAR). In a pre- and postnatal study in rats, pasireotide had no effect on labour or delivery at doses up to 10 mg/kg/day (45-fold MRHD for pasireotide LAR, based on body surface area). Pasireotide is excreted in milk. Retardation of physiological growth in the offspring was seen at 2 mg/kg/day (9-fold higher than the estimated maximum daily dose of Signifor LAR, based on body surface area). After weaning, body weight gains in the rat pups exposed to pasireotide were comparable to controls, showing reversibility. Pasireotide did not affect fertility in male rats at doses up to 10 mg/kg/day (45-fold higher than the estimated daily dose of Signifor LAR, based on body surface area). In female rats, as expected from the pharmacology of pasireotide, fertility was decreased at daily doses of 0.1 mg/kg/day (0.5-fold the estimated maximum daily dose of pasireotide LAR, based on body surface area), as shown by decreased numbers of live conceptions and implantation sites. A reduced number of corpora lutea and abnormal cycles or acyclicity were observed at 1 mg/kg/day. Other information Incompatibilities Signifor LAR powder for suspension for injection is to be used as a single-dose container and must not be mixed with other medicinal products. Therefore, no compatibility data with other products have been generated. Special precautions for storage Store in a refrigerator (2-8 C).

18 Page 18 of 22 Do not freeze. Keep out of the reach of children. Instructions for use and handling Instructions for preparation and intramuscular injection of Signifor LAR FOR DEEP INTRAMUSCULAR INJECTION ONLY ATTENTION: There are 2 critical steps in the reconstitution of Signifor LAR. Not following them could result in failure to deliver the drug properly to the site of action. The injection kit must be allowed to reach room temperature. Remove the injection kit from the refrigerator and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but on no account for longer than 24 hours. After adding the solvent, shake the vial gently in a horizontal direction for a minimum of 30 seconds until a uniform suspension is formed. Contents: a One vial containing Signifor LAR powder b One pre-filled syringe containing the solvent for reconstitution c One vial adapter for drug product reconstitution d One safety injection needle (20G 1.5") Follow the instructions below carefully to ensure proper reconstitution of Signifor LAR before performing deep intramuscular injection. Signifor LAR suspension must only be prepared immediately before injection. Signifor LAR should only be administered by a trained healthcare professional.

19 Page 19 of 22 Step 1 Remove the Signifor LAR injection kit from refrigerated storage. ATTENTION: It is essential to start the reconstitution process only after the injection kit reaches room temperature. Let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but on no account for longer than 24 hours. 30 min Note: The injection kit can be re-refrigerated if necessary. Step 2 Remove the plastic cap from the vial and disinfect the rubber stopper with an alcohol wipe. Remove the lid film of the vial adapter packaging, but do NOT remove the adapter from its packaging. Hold the adapter packaging and position the adapter on top of the vial. Then push the adapter fully down until it snaps into place, confirmed by an audible click. Now lift the packaging off the adapter with a vertical movement.

20 Page 20 of 22 Step 3 Remove the cap from the pre-filled syringe containing the solvent and screw the syringe onto the vial adapter. Cautiously push the plunger all the way down to transfer all the solvent into the vial. Step 4 ATTENTION: Keep the plunger pressed and shake the vial gently in a horizontal direction for a minimum of 30 seconds until the powder is completely suspended. Shake again gently for another 30 seconds if the powder is not completely suspended. Step 5 Turn the syringe and vial upside down (so the vial is on top), slowly pull the plunger back and draw the entire contents from the vial into the syringe. Unscrew the syringe from the adapter.

21 Page 21 of 22 Step 6 Screw the safety injection needle onto the syringe. Pull the protective cover straight off the needle. To avoid sedimentation, you may gently shake the syringe to maintain a uniform suspension. Gently tap the syringe with your finger to remove air bubbles, then expel them from the syringe. The reconstituted Signifor LAR is now ready for immediate administration. Step 7 Signifor LAR must be given only by deep intramuscular injection; NEVER intravenously. Disinfect the injection site with an alcohol wipe. Insert the needle fully into the left or right gluteal muscle at a 90 angle to the skin. Slowly pull back the plunger (aspirate) to check that no blood vessel has been penetrated (another injection site must be chosen if a blood vessel has been penetrated). Injection sites 90 angle Slowly depress the plunger until the syringe is empty. Withdraw the needle from the injection site and activate the needle guard (as shown in Step 8).

22 Page 22 of 22 Step 8 Activate the needle guard using one of the two methods described here: Either press the hinged section of the needle guard firmly down onto a hard surface (Figure A) or push the hinged section forward with your finger (Figure B). An audible click confirms proper activation. Dispose of the syringe immediately in a sharps container. Special precautions for disposal Any unused product or waste material should be properly disposed of in accordance with local requirements. Swissmedic number Pack sizes Signifor LAR 20 mg powder in a vial, solvent for suspension for injection in a pre-filled syringe. Signifor LAR 40 mg powder in a vial, solvent for suspension for injection in a pre-filled syringe. Signifor LAR 60 mg powder in a vial, solvent for suspension for injection in a pre-filled syringe. Marketing authorisation holder, Risch; Domicile: 6343 Rotkreuz, Switzerland Information last revised January 2015