Pasireotide

Evaluate fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), liver enzyme tests, electrocardiogram (ECG), serum magnesium, and serum potassium prior to starting. ( 2.1 ) Optimize glucose control in patients with poorly controlled diabetes mellitus prior to starting. ( 2.1 ) Must be administered by a health care professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. ( 2.2 ) Initial Dose: Acromegaly: The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days). ( 2.3 ) Cushing's Disease: The initial dose is 10 mg by intramuscular injection once every 4 weeks (every 28 days). ( 2.3 ) Adjust dose based on response and tolerability. ( 2.4 ) Patients with Hepatic Impairment: Child-Pugh B : Acromegaly: Recommended initial dose is 20 mg once every 4 weeks and maximum dose is 40 mg once every 4 weeks ( 2.5 , 8.6 ) Cushing's Disease: Recommended initial dose is 10 mg once every 4 weeks and maximum dose is 20 mg once every 4 weeks ( 2.5 , 8.6 ) Child-Pugh C : Avoid use in these patients ( 2.5 , 8.6 ) Follow reconstitution and administration instructions. ( 2.6 )

2.1 Recommended Baseline Evaluations Prior to Initiation of SIGNIFOR LAR Prior to the initiation of SIGNIFOR LAR, it is recommended that patients have the following baseline evaluations: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) [see Warnings and Precautions (5.1)] Liver tests [see Warnings and Precautions (5.3)] Electrocardiogram (ECG), serum potassium and serum magnesium levels [see Warnings and Precautions (5.2)] Patients with poorly controlled diabetes mellitus, who have inadequate glucose control, should have anti-diabetic therapy optimized prior to starting SIGNIFOR LAR [see Warnings and Precautions (5.1)] .

2.2 Important Administration Instructions SIGNIFOR LAR must be reconstituted by a trained healthcare professional immediately before use. Illustrations on reconstitution are found in Instructions for Use [see Dosage and Administration (2.6)] . SIGNIFOR LAR must be inspected visually before use. The suspension should appear free of foreign particulates and should be homogeneous after mixing. SIGNIFOR LAR must be administered by a trained healthcare professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR LAR must never be administered intravenously.

2.3 Recommended Initial Dose Acromegaly The recommended initial dose of SIGNIFOR LAR for the treatment of acromegaly is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6) ]. Cushing's Disease The recommended initial dose of SIGNIFOR LAR for the treatment of Cushing's disease is 10 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6) ].

2.4 Dose Adjustment and Monitoring Acromegaly The dose may be increased to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age and sex adjusted insulin-like growth factor-1 (IGF-1) levels after 3 months of treatment with SIGNIFOR LAR at 40 mg and who tolerate this dose. Management of SIGNIFOR LAR-related adverse reactions or over-response to treatment (age and sex adjusted IGF-1 less than the lower limit of normal) may require dose reduction. The dose may be decreased, either temporarily or permanently, by 20 mg decrements [see Warnings and Precautions (5)] . Cushing's Disease Following 4 months of treatment with the initial dose of 10 mg once every 28 days, the dose may be increased for patients who have not normalized 24-hour urinary free cortisol (UFC) and who tolerate this dose, up to a maximum dose of 40 mg once every 28 days. Management of suspected adverse reactions or over-response to treatment (e.g., cortisol levels less than the lower limit of the normal range or in the low part of the normal range in patients with symptoms suggestive of adrenal insufficiency) may require dose reduction to the previous tolerated dose, dose interruption, or drug discontinuation of SIGNIFOR LAR. For patients treated with 10 mg once every 28 days, the dose may be either interrupted or discontinued [see Warnings and Precautions (5)] .

2.5 Dose in Patients With Hepatic Impairment For patients with moderately impaired hepatic function (Child-Pugh B) [see Use in Specific Populations (8.6) ] : Acromegaly: The recommended initial dose for acromegaly patients with moderately impaired hepatic function is 20 mg once every 4 weeks and the maximum recommended dose is 40 mg once every 4 weeks. Cushing's Disease: The recommended initial dose for Cushing's disease patients with moderately impaired hepatic function is 10 mg once every 4 weeks and the maximum recommended dose is 20 mg once every 4 weeks. Avoid use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)] .

2.6 Reconstitution and Intramuscular Injection Instructions After reconstitution of the SIGNIFOR LAR vial with the provided 2 mL diluent, the intramuscular injectable suspension will have a final concentration of: Strength per Vial Final Concentration When Reconstituted (total product strength per total volume) Final Concentration When Reconstituted (per mL) 10 mg 10 mg/2 mL 5 mg/mL 20 mg 20 mg/2 mL 10 mg/mL 30 mg 30 mg/2 mL 15 mg/mL 40 mg 40 mg/2 mL 20 mg/mL 60 mg 60 mg/2 mL 30 mg/mL The entire contents of the reconstituted solution should be administered immediately. PAY PARTICULAR ATTENTION: There are 2 critical steps in the reconstitution of SIGNIFOR LAR. Not following these 2 steps could result in failure to deliver the drug appropriately . 1) The injection kit must reach room temperature (see Step 1 in Instructions for Use) . Remove the SIGNIFOR LAR injection kit from refrigerated storage and let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours. 2) After adding the diluent solution, shake the vial moderately in a horizontal direction for a minimum of 30 seconds until uniform suspension is formed (see Step 4 in Instructions for Use) . The following items are included in the injection kit : a) One vial containing SIGNIFOR LAR powder b) One prefilled syringe containing the diluent solution for reconstitution c) One vial adapter for drug product reconstitution d) One safety injection needle (20G x 1.5") Figure 1. Items Included in Injection Kit SIGNIFOR LAR suspension must only be reconstituted immediately before administration. Follow the directions in the Instructions for Use to ensure proper reconstitution of SIGNIFOR LAR before intramuscular injection. SIGNIFOR LAR should only be administered by a trained healthcare professional. Instructions for Use Step 1 Remove the SIGNIFOR LAR for injectable suspension kit from refrigerated storage. PAY PARTICULAR ATTENTION: It is essential to start the reconstitution process only after the injection kit has reached room temperature. Let the kit stand at room temperature for at least 30 minutes before starting reconstitution, but not more than 24 hours. Note: The kit can be re-refrigerated if needed. Step 2 Remove the plastic cap from the vial and clean the rubber stopper with an alcohol wipe. Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging. Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place. You will hear an audible "click" when the vial adapter snaps in place. Lift the packaging off the vial adapter with a vertical movement. Step 3 Remove the cap from the syringe prefilled with diluent solution and screw the syringe onto the vial adapter. Slowly push the plunger all the way down to transfer all the diluent solution in the vial. Step 4 ATTENTION: Keep the plunger pressed and shake the vial moderately in a horizontal direction for a minimum of 30 seconds so that the powder is completely suspended . Repeat moderate shaking for another 30 seconds if the powder is not completely suspended . Step 5 Turn the syringe and vial upside down, slowly pull the plunger back and draw the entire content from the vial into the syringe. Unscrew the syringe from the vial adapter. Step 6 Screw the safety injection needle onto the syringe. Pull the protective cover straight off the needle. To avoid sedimentation and maintain a uniform suspension, you may gently shake the syringe. Gently tap the syringe to remove any visible bubbles and expel them from the syringe. The reconstituted SIGNIFOR LAR is now ready for immediate administration. Step 7 SIGNIFOR LAR must only be given by intramuscular injection and NEVER intravenously. Prepare the injection site by wiping with an alcohol wipe. Insert the needle fully into the left or right gluteus at a 90° angle to the skin. Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated). Slowly depress the plunger until the syringe is empty. Withdraw the needle from the injection site and activate the safety guard (as shown in Step 8). Step 8 Activate the safety guard over the needle using 1 of the 2 methods shown:

• either press the hinged section of the safety guard down onto a hard surface (Figure A),
• or push the hinge forward with your finger (Figure B). An audible "click" will confirm proper activation of the safety guard. Dispose of syringe immediately in a sharps container. Any unused product or waste material should be disposed of in accordance with local requirements. Included in the injection kit: Step 1 Step 2 Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging. Lift the packaging off the vial adapter with a vertical movement. Step 3 Slowly push the plunger all the way down to transfer all the diluent solution in the vial. Step 4 Step 5 Unscrew the syringe from the vial adapter. Step 6 Pull the protective cover straight off the needle. Step 7 Step 8 2.7 Missed Dose If a dose is missed and the patient returns prior to the next scheduled dose, a dose may be given up to but no later than 14 days prior to the next dose.

5 WARNINGS AND PRECAUTIONS Hyperglycemia, Diabetes, and Ketoacidosis: Sometimes severe. Monitor glucose levels as clinically appropriate during therapy. Monitor glucose levels more frequently in the months that follow initiation or discontinuation of SIGNIFOR LAR therapy and following SIGNIFOR LAR dose adjustment. Use anti-diabetic treatment if indicated.If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient. ( 2.1 , 5.1 ) Bradycardia and QT Prolongation: Use with caution in at-risk patients; evaluate ECG and electrolytes prior to dosing and periodically while on treatment. ( 2.1 , 5.2 , 7.1 ) Liver Test Elevations: Evaluate liver enzyme tests prior to and during treatment. ( 2.1 , 5.3 ) Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected. ( 5.4 ) Pituitary Hormone Deficiency(ies): Monitor for occurrence periodically and treat if clinically indicated. ( 5.5 ) Steatorrhea and Malabsorption of Dietary Fats : New onset steatorrhea, stool discoloration, loose stools, abdominal bloating, and weight loss may occur. If new occurrence or worsening of these symptoms are reported, evaluate for potential pancreatic exocrine insufficiency ( 5.6 )

5.1 Hyperglycemia, Diabetes, and Ketoacidosis SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes. In the acromegalic patient study, 5 patients naïve to drug therapy treated with SIGNIFOR LAR (2 of whom were normoglycemic at baseline) and none in the active comparator group were hospitalized for hyperglycemia (blood glucose range 359-506 mg/dL). Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial, were hospitalized for elevated glucose levels while on SIGNIFOR LAR; one of those patients developed diabetic ketoacidosis. In the Cushing's disease study, 2 patients were hospitalized for elevated blood glucose. In clinical studies for acromegaly and Cushing's disease, SIGNIFOR LAR caused an increase in the incidence of diabetes and prediabetes. A majority of patients, including those with normal glucose tolerance, prediabetes and diabetes, experienced increased glucose levels within the first 3 months of treatment [see Adverse Reactions (6.1) ]. In the drug-naïve acromegaly study, the prevalence of diabetes increased from 30% at baseline to 60% at Month 12. In the study evaluating acromegaly patients previously treated with somatostatin analogs, the prevalence of diabetes increased from 71% at baseline to 87% at Month 6 in patients treated with SIGNIFOR LAR 40 mg, and from 60% to 84% in patients treated with SIGNIFOR LAR 60 mg. In the Cushing's disease study, the prevalence of diabetes increased from 40% at baseline to 56% at Month 12. Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess FPG and HbA1c prior to starting treatment with SIGNIFOR LAR [see Dosage and Administration (2.1)] . In patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before SIGNIFOR LAR initiation. Monitor blood glucose weekly for the first 3 months after initiating SIGNIFOR LAR and the first 4- to 6 weeks after dose increases. Continue monitoring thereafter, as clinically appropriate. Patients who develop significant hyperglycemia on SIGNIFOR LAR may require initiation of anti-diabetic treatment or adjustment in their current anti-diabetic treatment. The optimal treatment for the management of SIGNIFOR LAR-induced hyperglycemia is not known. If hyperglycemia cannot be controlled despite medical management, reduce the dose of SIGNIFOR LAR or discontinue SIGNIFOR LAR. Assess FPG and HbA1c after SIGNIFOR LAR discontinuation, if indicated. Patients receiving anti-diabetic treatment may require more frequent blood glucose monitoring and dose adjustment to their anti-diabetic drug therapy to mitigate the risk of hypoglycemia after discontinuing SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. In some reported post-marketing cases of ketoacidosis in patients taking SIGNIFOR LAR, factors predisposing to ketoacidosis such as acute illness, infection, pancreatic disorders (e.g., pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

5.2 Bradycardia and QT Prolongation Bradycardia Bradycardia has been reported with the use of SIGNIFOR LAR [see Adverse Reactions (6.1)] . Patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia, high-grade heart block, or concomitant use of drugs associated with bradycardia, should be monitored. Adjustments in the dose of drugs known to slow the heart rate (e.g., beta-blockers, calcium channel blockers) and correction of electrolyte disturbances may be necessary when initiating or during the course of SIGNIFOR LAR treatment. QT Prolongation In cardiac electrophysiology studies (i.e., thorough QT studies) with pasireotide via subcutaneous route, QT prolongation occurred at therapeutic and supra-therapeutic doses [see Clinical Pharmacology (12.2)] . In the clinical studies, a corrected QT interval (i.e., QTcF) of greater than 480 ms was reported in 6 patients and an increase in the QTcF from baseline of greater than 60 ms was reported for seven patients on SIGNIFOR LAR. No patient on SIGNIFOR LAR had a QTcF value of greater than 500 ms [see Adverse Reactions (6.1) , Clinical Pharmacology (12.2) ] . SIGNIFOR LAR should be used with caution in patients who are at significant risk of developing prolongation of the QT interval, such as those listed below: with congenital long QT prolongation with uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia on anti-arrhythmic therapy or other substances that are known to lead to QT prolongation with hypokalemia and/or hypomagnesemia A baseline ECG is recommended prior to initiating therapy with SIGNIFOR LAR. Monitoring for an effect on the QT interval at the time of maximum drug concentration (21 days after injection) should be obtained in patients at risk. Hypokalemia or hypomagnesemia must be corrected prior to initiating SIGNIFOR LAR and should be monitored periodically during therapy.

5.3 Liver Test Elevations Increases in liver enzymes have been observed with SIGNIFOR LAR. In all Phase 3 acromegaly studies and across all doses, alanine aminostransferase (ALT) or aspartate aminotransferase (AST) elevations greater than 3 times the upper limit of normal (ULN) were observed in 4% of acromegaly patients and ALT or AST elevations greater than 5 times the ULN were observed in 1% of acromegaly patients treated with SIGNIFOR LAR. In the Phase 3 Cushing's disease study and across all doses, ALT or AST elevations greater than 3 times the ULN were observed in 14% of Cushing's disease patients and ALT or AST elevations greater than 5 times the ULN were observed in 5% of Cushing's disease patients treated with SIGNIFOR LAR. Assessment of liver function is recommended prior to treatment with SIGNIFOR LAR , and after the first 2- to 3 weeks, then monthly for 3 months. Thereafter, liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels, should be monitored until values return to pre-treatment levels. Treatment with SIGNIFOR LAR should be discontinued if signs or symptoms suggestive of clinically significant liver impairment develop. 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.

5.4 Cholelithiasis and Complications of Cholelithiasis Cholelithiasis was reported in 33% of drug-naïve and 10% of inadequately controlled (40 mg dose) acromegaly patients treated with SIGNIFOR LAR in clinical trials [see Adverse Reactions (6)] . Cholelithiasis was reported in 33% of Cushing's disease patients treated with SIGNIFOR LAR. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis or cholangitis and requiring cholecystectomy in patients taking SIGNIFOR LAR. Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue SIGNIFOR LAR and treat appropriately.

5.5 Pituitary Hormone Deficiency(ies) Suppression of anterior pituitary hormones may occur on SIGNIFOR LAR. Monitoring pituitary function (e.g., thyroid, adrenal, gonadal) prior to initiation of therapy with SIGNIFOR LAR, as well as periodically during treatment, as clinically appropriate, is recommended. Patients should be monitored for and instructed on the signs and symptoms of adrenal insufficiency during therapy. If adrenal insufficiency is suspected, it should be confirmed and treated per standard of care with exogenous glucocorticoids at replacement doses .

5.6 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stools have been reported in patients receiving somatostatin analogs, including pasireotide products. Somatostatin analogs reversibly inhibit secretion of pancreatic enzymes and bile acids, which may result in malabsorption of dietary fats and subsequent symptoms of steatorrhea, loose stools, abdominal bloating, and weight loss. If new occurrence or worsening of these symptoms are reported in patients receiving SIGNIFOR LAR, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly.

Clinically significant adverse reactions that appear in other sections of the labeling include: Hyperglycemia, Diabetes, and Ketoacidosis [see Warnings and Precautions (5.1)] Bradycardia and QT Prolongation [see Warnings and Precautions (5.2)] Liver Test Elevations [see Warnings and Precautions (5.3)] Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.4)] Pituitary Hormone Deficiency(ies) [see Warnings and Precautions (5.5)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.6) ] Adverse drug reactions associated with SIGNIFOR LAR and occurring in ≥ 20% of patients were diarrhea, cholelithiasis, hyperglycemia, and diabetes mellitus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Drug-Naïve Patients With Acromegaly The data described in Table 1 are derived from an active-controlled trial in patients with acromegaly naïve to previous drug therapy [see Clinical Studies (14.1)] . The data reflect exposure of 178 patients with acromegaly to SIGNIFOR LAR for a mean duration of 43 weeks. In the overall study population, 52% were female and the average age of patients was 45 years. Table 1 presents common adverse reactions associated with SIGNIFOR LAR in this study. These adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 1 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Naïve to Drug Therapy a Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus. b Sinus bradycardia includes the following PTs: bradycardia and sinus bradycardia. c Injection-site reaction related AEs includes the following PTs: injection-site pain, injection-site reaction, injection-site haematoma, injection-site pruritus, injection-site swelling, injection-site erythema. Adverse Reaction Type SIGNIFOR LAR (40-60 mg) % N = 178 Active Comparator % N = 180 Hyperglycemia Related Adverse Reactions Hyperglycemia 29 8 Diabetes mellitus a 26 4 Blood glucose increased 8 2 Glycosylated hemoglobin increased 6 2 Hypoglycemia 5 7 Gastrointestinal Related Adverse Reactions Diarrhea 39 45 Abdominal pain 18 22 Nausea 14 22 Abdominal distension 12 12 Vomiting 8 7 Abdominal pain upper 6 8 Hepatobiliary Related Adverse Reactions Cholelithiasis 26 36 Cardiac Related Adverse Reactions Sinus bradycardia b 10 7 Hypertension 8 7 Nervous System Related Adverse Reactions Headache 19 26 Dizziness 10 11 Skin Related Adverse Reactions Alopecia 18 19 Infections Related Adverse Reactions Nasopharyngitis 16 16 Influenza 8 4 Upper respiratory tract infection 7 3 Cough 5 8 Laboratory Related Adverse Reactions Blood creatine phosphokinase increased 13 12 Alanine aminotransferase increased 8 4 Aspartate aminotransferase increased 6 4 Lipase increased 6 7 Weight decreased 5 4 General and Injection-Site Related Adverse Reactions Fatigue 10 10 Injection-site reaction c 7 7 Musculoskeletal and Connective Tissue Related Adverse Reactions Arthralgia 10 12 Back pain 8 11 Pain in extremity 7 4 Blood Related Adverse Reactions Anemia 6 6 Other notable adverse reactions which occurred with a frequency of 5% or less for SIGNIFOR LAR were: adrenal insufficiency (3%); glucose tolerance impaired (1%); QT-prolongation (4%); blood amylase increased (2%). Patients With Acromegaly Inadequately Controlled on Other Somatostatin Analogs at Baseline The data described in Table 2 are derived from an active-controlled study in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs [see Clinical Studies (14.2)] . These data reflect exposure of 63 and 62 patients to SIGNIFOR LAR 40 mg and 60 mg, respectively, for a mean duration of 24 weeks. In the overall study population, 56% were female and the average age of patients was 45 years. Table 2 presents common adverse reactions associated with SIGNIFOR LAR in this study. These common adverse reactions were not present at baseline, or if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 2 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Acromegaly Previously Treated With Other Somatostatin Analogs a Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus. Adverse Drug Reactions SIGNIFOR LAR 40 mg % N = 63 SIGNIFOR LAR 60 mg % N = 62 Active Comparators % N = 66 Hyperglycemia Related Adverse Reactions Hyperglycemia 33 30 14 Diabetes mellitus a 21 31 9 Blood glucose increased 5 7 0 Hypoglycemia 3 7 0 Gastrointestinal Related Adverse Reactions Diarrhea 16 19 5 Abdominal pain 8 8 3 Nausea 3 7 3 Hepatobiliary Related Adverse Reactions Cholelithiasis 10 13 14 Cardiac Related Adverse Reactions Atrioventricular block first degree 6 0 0 Nervous System Related Adverse Reactions Headache 14 3 5 Dizziness 8 2 3 Skin and Subcutaneous Tissue Related Adverse Reactions Alopecia 2 7 0 Infections Related Adverse Reactions Nasopharyngitis 6 11 3 Blood Related Adverse Reactions Anemia 6 3 3 Other notable adverse reactions which occurred with a frequency of 5% or less in the SIGNIFOR LAR 40 mg, SIGNIFOR LAR 60 mg arm, respectively, were adrenal insufficiency (2% and 0%) and glucose tolerance impaired (3% and 5%). Patients With Cushing's Disease The data described in Table 3 are derived from a randomized clinical study in 150 patients with Cushing's disease [see Clinical Studies (14.3)] . These data reflect exposure of 74 and 76 patients to SIGNIFOR LAR at a starting dose of 10 mg and 30 mg once every 28 days, respectively, for a mean duration of 68 weeks. In the overall study population, 79% of patients were female and the average age was 39 years at study entry. Table 3 presents common adverse reactions which were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 3 – Adverse Reactions Occurring in Greater Than or Equal to 5% of Patients Exposed to SIGNIFOR LAR in Patients With Cushing's Disease a Diabetes mellitus consists of the two terms: diabetes mellitus and type 2 diabetes mellitus. b Abdominal pain includes the term abdominal pain upper. c Sinus bradycardia includes the term bradycardia. d Fatigue includes the term asthenia. Adverse Reactions Overall % N = 150 Endocrine Related Adverse Reactions Adrenal insufficiency 7 Blood cortisol decreased 5 Hyperglycemia Related Adverse Reactions Hyperglycemia 47 Diabetes mellitus a 27 Hypoglycemia 15 Blood glucose increased 9 Glycosylated hemoglobin (HbA1C) increased 5 Gastrointestinal Related Adverse Reactions Diarrhea 39 Nausea 21 Abdominal pain b 23 Constipation 7 Abdominal distension 5 Flatulence 5 Vomiting 5 Hepatobiliary Related Adverse Reactions Cholelithiasis 33 Gamma-glutamyltransferase increased 9 Alanine aminotransferase increased 7 Cardiac Related Adverse Reactions Hypertension 15 Hypotension 6 Sinus bradycardia c 5 General Related Adverse Reactions Fatigue d 27 Edema peripheral 14 Musculoskeletal and Connective Tissue Related Adverse Reactions Back pain 11 Arthralgia 8 Pain in extremity 7 Myalgia 5 Metabolism and Nutrition Related Adverse Reactions Decreased appetite 10 Hyperuricemia 7 Hypercholesterolemia 6 Blood Related Adverse Reactions Anemia 5 Other adverse reactions which occurred at a frequency less than 5% were cholestasis (4%), glucose tolerance impaired (3%), aspartate aminotransferase increased (3%), vomiting (3%), lipase increased (3%), injection-site reactions (2%), ECG QT prolonged (1%), cholecystitis (1%), amylase increased (1%), and prothrombin time prolonged (1%). Hyperglycemia The average FPG levels in patients with acromegaly naïve to drug therapy study [see Clinical Studies (14.1)] across visits is shown in Figure 2 below. Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy Numbers of patients with a glucose value at the given timepoint in the SIGNIFOR LAR/Active comparator arms are displayed as xxx/xxx on the x axis. Pancreatic Enzyme Elevation and Pancreatitis Asymptomatic elevations in lipase and alpha amylase were observed in 30% and 20% of patients receiving SIGNIFOR LAR in the drug naïve study in acromegaly, and in 1% and 3% of patients receiving SIGNIFOR LAR in the study of acromegaly patients previously treated. In the drug-naïve study, 2 acromegaly patients receiving SIGNIFOR LAR developed pancreatitis. In the Cushing's disease study, increased lipase was observed in 4% of patients, and 1 patient developed pancreatitis. Pancreatitis is a potential adverse reaction associated with the use of SIGNIFOR LAR due to the association between cholelithiasis and acute pancreatitis. Figure 2. Mean Fasting Plasma Glucose (mg/dL) By Visit in the Study of Patients With Acromegaly Naïve to Drug Therapy* 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of SIGNIFOR LAR. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cholelithiasis resulting in complications, including cholecystitis and cholangitis, which have sometimes required cholecystectomy

Females and Males of Reproductive Potential : Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 )

8.1 Pregnancy Risk Summary The limited data with SIGNIFOR LAR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryo-fetal development studies in rabbits, findings indicating a developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In embryo-fetal development studies in rats given 1 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 12 times higher than that at the maximum therapeutic dose based on area under the curve (AUC) comparisons across species. An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 106 times the exposure in humans at the highest recommended dose of 60 mg SIGNIFOR LAR administered as an intramuscular injection once every 4 weeks. In embryo-fetal development studies in rabbits given 0.05 mg/kg/day, 1 mg/kg/day, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 5 times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose. In pre- and post-natal developmental studies in rats given subcutaneous doses of 2 mg/kg/day, 5 mg/kg/day, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (9 times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay.

8.2 Lactation Risk Summary There is no information available on the presence of SIGNIFOR LAR in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that pasireotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SIGNIFOR LAR, and any potential adverse effects on the breastfed child from SIGNIFOR LAR or from the underlying maternal condition. Data Available data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg [ 14 C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity was 0.28, based on AUC 0-∞ values.

8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of IGF-1 in acromegalic females treated with pasireotide may lead to improved fertility. Similarly, the therapeutic benefits of a reduction or normalization of serum cortisol levels in female patients with Cushing's disease treated with pasireotide may also lead to improved fertility.

8.4 Pediatric Use Safety and effectiveness of SIGNIFOR LAR have not been established in pediatric patients.

8.5 Geriatric Use Clinical studies of SIGNIFOR LAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)] .

8.7 Renal Impairment Clinical studies of SIGNIFOR LAR in patients with renal impairment have not been conducted. On the basis of studies with pasireotide given subcutaneously, dosage adjustment is not needed in patients with renal impairment [see Clinical Pharmacology (12.3)] .

12.1 Mechanism of Action SIGNIFOR LAR is an injectable cyclohexapeptide, somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTR). There are 5 known human somatostatin receptor subtypes: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogs bind to SSTRs with different potencies. Pasireotide binds with high affinity to 4 of the 5 SSTRs (see Table 4). Table 4 – Binding Affinities of Somatostatin (SRIF-14) and Pasireotide to the Five Human SSTR Subtypes (SSTR 1-5) Results are the mean + SEM of IC 50 values expressed as nmol/l (nM). Compound SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Somatostatin (SRIF-14) 0.93 ± 0.12 0.15 ± 0.02 0.56 ± 0.17 1.5 ± 0.4 0.29 ± 0.04 Pasireotide 9.3 ± 0.1 1.0 ± 0.1 1.5 ± 0.3 > 100 0.16 ± 0.01 12.2 Pharmacodynamics Somatostatin receptors are expressed in many tissues including neuroendocrine tumors (e.g., growth hormone or adrenocorticotropic hormone secreting pituitary adenomas). Acromegaly Pasireotide binds to SSTR2 and SSTR5 subtype receptors which may be relevant for inhibition of GH secretion. In vivo studies show that SIGNIFOR LAR lowers GH and IGF-1 levels in patients with acromegaly. Cushing's Disease Corticotroph tumor cells from Cushing's disease patients frequently over-express SSTR5 whereas the other receptor subtypes are often not expressed or are expressed at lower levels. Pasireotide binds and activates the SSTRs resulting in inhibition of ACTH secretion, which leads to decreased cortisol secretion. Cardiac Electrophysiology Individually corrected QT (QTcI) interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide subcutaneous doses of 0.6 mg and 1.95 mg twice daily, respectively. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg twice daily, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg twice daily. The predicted pasireotide peak concentration (25.8 ng/mL) following SIGNIFOR LAR 60-mg dose in acromegaly patients is similar to the observed peak concentration (24.3 mg/mL) of the subcutaneous SIGNIFOR 0.6 mg twice daily dose and below the observed peak concentration (80.6 ng/mL) of the subcutaneous SIGNIFOR 1.95 mg twice daily dose. The predicted pasireotide peak concentration for the SIGNIFOR LAR dose of 40 mg in Cushing's disease patients is 14 ng/mL.

12.3 Pharmacokinetics Pasireotide for intramuscular use is formulated as microspheres for long-acting release. After a single injection, the plasma pasireotide concentration shows an initial burst release on the injection day, followed by a dip from Day 2 to Day 7, then a slow increase to the maximum concentration around Day 21, and a slow declining phase over the next weeks, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. Absorption and Distribution No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR LAR is administered via a parenteral route. In healthy volunteers, pasireotide administered as SIGNIFOR LAR is widely distributed with large apparent volume of distribution (V z /F > 100 L). Distribution between blood and plasma is concentration-independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration. Pasireotide has low passive permeability and is likely to be a substrate of P-glycoprotein (P-gp), but the impact of P-gp on the ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition did not affect the rate or extent of pasireotide availability [see Drug Interactions (7.1)] . At therapeutic dose levels, pasireotide is not expected to be a substrate of BCRP (breast cancer resistance protein), OCT1 (organic cation transporter 1), or OATP (organic anion-transporting polypeptides) 1B1, 1B3, or 2B1. Elimination Metabolism and Excretion Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of GH secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes. Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study with subcutaneous SIGNIFOR with a single dose 0.6 mg, 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine. The apparent clearance (CL/F) of SIGNIFOR LAR in healthy volunteers is on average 4.5-8.5 L/hour. Steady-State Pharmacokinetics PK steady-state for SIGNIFOR LAR is achieved after 3 monthly doses. Following multiple intramuscular doses every 4 weeks (every 28 days), SIGNIFOR LAR demonstrates approximately dose-proportional PK exposures (steady-state trough; Ctrough, ss) in the dose range of 10 mg to 60 mg every 4 weeks. Special Populations Population PK analyses of SIGNIFOR LAR suggest that race, gender, and body weight do not have clinically relevant influence on circulating levels of pasireotide. No dose adjustment is required for demographics. Pediatric Patients No studies have been performed in pediatric patients [see Use in Specific Populations (8.4)] . Geriatric Patients Age is not a significant covariate in the population PK analysis. Therefore age is not expected to significantly impact circulating levels of pasireotide. Efficacy and safety data on patients older than 65 years are limited [see Use in Specific Populations (8.5)] . Hepatic Impairment In a clinical study with a single subcutaneous dose of 600 µg pasireotide in subjects with impaired hepatic function (Child-Pugh A, B, and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparing with the control group, AUC inf was increased by 12%, 56%, and 42%; and C max was increased by 3%, 46%, and 33% respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations (8.6), Dosage and Administration (2.5)] . Renal Impairment Clinical studies have not been performed in patients with renal impairment. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function (creatinine clearance and estimated glomerular filtration rate) is not a covariate in the population PK analysis. Therefore, renal function is not expected to significantly impact the circulating levels of pasireotide [see Use in Specific Populations (8.7)] .