Sandostatin

1 INDICATIONS AND USAGE SANDOSTATIN LAR DEPOT 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with Sandostatin Injection has been shown to be effective and tolerated. SANDOSTATIN LAR DEPOT is a somatostatin analogue indicated for: Treatment in patients who have responded to and tolerated Sandostatin Injection subcutaneous injection for: Acromegaly ( 1.1 ) Severe diarrhea/flushing episodes associated with metastatic carcinoid tumors ( 1.2 ) Profuse watery diarrhea associated with Vasoactive Intestinal Peptide (VIP) secreting tumors ( 1.3 ) 1.1 Acromegaly Long-term maintenance therapy in acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy, is not an option. The goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal [see Clinical Studies (14), Dosage and Administration (2)] . 1.2 Carcinoid Tumors Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors. 1.3 Vasoactive Intestinal Peptide Tumors (VIPomas) Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors. 1.4 Important Limitations of Use In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and SANDOSTATIN LAR DEPOT on tumor size, rate of growth and development of metastases, has not been determined.

2 DOSAGE AND ADMINISTRATION SANDOSTATIN LAR DEPOT should be administered by a trained healthcare provider. It is important to closely follow the mixing instructions included in the packaging. SANDOSTATIN LAR DEPOT must be administered immediately after mixing. Do not directly inject diluent without preparing suspension. The recommended needle size for administration of SANDOSTATIN LAR DEPOT is the 1½” 19 gauge safety injection needle (supplied in the drug product kit). For patients with a greater skin to muscle depth, a size 2” 19 gauge needle (not supplied) may be used. SANDOSTATIN LAR DEPOT should be administered intramuscularly (IM) in the gluteal region at 4-week intervals. Administration of SANDOSTATIN LAR DEPOT at intervals greater than 4 weeks is not recommended. Injection sites should be rotated in a systematic manner to avoid irritation. Deltoid injections should be avoided due to significant discomfort at the injection site when given in that area. SANDOSTATIN LAR DEPOT should never be administered intravenously or subcutaneously. The following dosage regimens are recommended. Patients Not Currently Receiving Sandostatin Injection Subcutaneously: Acromegaly: 50 mcg three times daily Sandostatin Injection subcutaneously for 2 weeks followed by SANDOSTATIN LAR DEPOT 20 mg intragluteally every 4 weeks for 3 months ( 2.1 ) Carcinoid Tumors and VIPomas: Sandostatin Injection subcutaneously 100 to 600 mcg/day in 2-4 divided doses for 2 weeks followed by SANDOSTATIN LAR DEPOT 20 mg every 4 weeks for 2 months ( 2.2 ) Patients Currently Receiving Sandostatin Injection Subcutaneously: Acromegaly: 20 mg every 4 weeks for 3 months ( 2.1 ) Carcinoid Tumors and VIPomas: 20 mg every 4 weeks for 2 months ( 2.2 ) Renal Impairment, Patients on Dialysis: 10 mg every 4 weeks ( 2.3 ) Hepatic Impairment, Patients With Cirrhosis: 10 mg every 4 weeks ( 2.4 ) 2.1 Acromegaly Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously in an initial dose of 50 mcg three times daily which may be titrated. Most patients require doses of 100 mcg to 200 mcg three times daily for maximum effect but some patients require up to 500 mcg three times daily. Patients should be maintained on Sandostatin Injection subcutaneous for at least 2 weeks to determine tolerance to octreotide acetate. Patients who are considered to be “responders” to the drug, based on GH and IGF-1 levels and who tolerate the drug, can then be switched to SANDOSTATIN LAR DEPOT in the dosage scheme described below (Patients Currently Receiving Sandostatin Injection). Patients Currently Receiving Sandostatin Injection Patients currently receiving Sandostatin Injection can be switched directly to SANDOSTATIN LAR DEPOT in a dose of 20 mg given IM intragluteally at 4-week intervals for 3 months. After 3 months, dosage may be adjusted as follows: GH ≤ 2.5 ng/mL, IGF-1 normal, and clinical symptoms controlled: maintain SANDOSTATIN LAR DEPOT dosage at 20 mg every 4 weeks GH > 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase SANDOSTATIN LAR DEPOT dosage to 30 mg every 4 weeks GH ≤ 1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce SANDOSTATIN LAR DEPOT dosage to 10 mg every 4 weeks If GH, IGF-1, or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks. Doses higher than 40 mg are not recommended. In patients who have received pituitary irradiation, SANDOSTATIN LAR DEPOT should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, SANDOSTATIN LAR DEPOT therapy may be resumed. 2.2 Carcinoid Tumors and VIPomas Patients Not Currently Receiving Octreotide Acetate Patients not currently receiving octreotide acetate should begin therapy with Sandostatin Injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg). Some patients may require doses up to 1,500 mcg/day. The suggested daily dosage for VIPomas is 200 to 300 mcg in 2 to 4 divided doses (range, 150 to 750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required. Sandostatin Injection should be continued for at least 2 weeks. Thereafter, patients who are considered “responders” to octreotide acetate, and who tolerate the drug, may be switched to SANDOSTATIN LAR DEPOT in the dosage regimen as described below (Patients Currently Receiving Sandostatin Injection). Patients Currently Receiving Sandostatin Injection Patients currently receiving Sandostatin Injection can be switched to SANDOSTATIN LAR DEPOT in a dosage of 20 mg given IM intragluteally at 4-week intervals for 2 months. Because of the need for serum octreotide to reach therapeutically effective levels following initial injection of SANDOSTATIN LAR DEPOT, carcinoid tumor and VIPoma patients should continue to receive Sandostatin Injection subcutaneously for at least 2 weeks in the same dosage they were taking before the switch. Failure to continue subcutaneous injections for this period may result in exacerbation of symptoms (some patients may require 3 or 4 weeks of such therapy). After 2 months, dosage may be adjusted as follows: If symptoms are adequately controlled, consider a dose reduction to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Many patients can, however, be satisfactorily maintained at a 10-mg dose every 4 weeks. If symptoms are not adequately controlled, increase SANDOSTATIN LAR DEPOT to 30 mg every 4 weeks. Patients who achieve good control on a 20-mg dose may have their dose lowered to 10 mg for a trial period. If symptoms recur, dosage should then be increased to 20 mg every 4 weeks. Dosages higher than 30 mg are not recommended. Despite good overall control of symptoms, patients with carcinoid tumors and VIPomas often experience periodic exacerbation of symptoms (regardless of whether they are being maintained on Sandostatin Injection or SANDOSTATIN LAR DEPOT). During these periods, they may be given Sandostatin Injection subcutaneously for a few days at the dosage they were receiving prior to switching to SANDOSTATIN LAR DEPOT. When symptoms are again controlled, the Sandostatin Injection subcutaneous can be discontinued. 2.3 Special Populations: Renal Impairment In patients with renal failure requiring dialysis, the starting dose should be 10 mg every 4 weeks. In other patients with renal impairment, the starting dose should be similar to a nonrenal patient (i.e., 20 mg every 4 weeks) [see Clinical Pharmacology (12)] . 2.4 Special Populations: Hepatic Impairment – Cirrhotic Patients In patients with established cirrhosis of the liver, the starting dose should be 10 mg every 4 weeks [see Clinical Pharmacology (12.3)] .

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected ( 5.1 ) Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment ( 5.2 ) Thyroid Function: Hypothyroidism may occur. Monitor thyroid levels periodically ( 5.3 ) Cardiac Function: Bradycardia, arrhythmia, or conduction abnormalities may occur. Use with caution in at-risk patients ( 5.4 ) 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 ( 5.5 ) 5.1 Cholelithiasis and Complications of Cholelithiasis SANDOSTATIN LAR DEPOT may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. There have been postmarketing reports of cholelithiasis (gallstones) resulting in complications, including cholecystitis, cholangitis, pancreatitis and requiring cholecystectomy in patients taking SANDOSTATIN LAR DEPOT [see Adverse Reactions (6)] . Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue SANDOSTATIN LAR DEPOT and treat appropriately. 5.2 Hyperglycemia and Hypoglycemia Octreotide alters the balance between the counter-regulatory hormones, insulin, glucagon, and growth hormone (GH), which may result in hypoglycemia or hyperglycemia. Blood glucose levels should be monitored when SANDOSTATIN LAR DEPOT treatment is initiated, or when the dose is altered. Anti-diabetic treatment should be adjusted accordingly [see Adverse Reactions (6)] . 5.3 Thyroid Function Abnormalities Octreotide suppresses the secretion of thyroid-stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total and/or free T 4 ) is recommended during chronic octreotide therapy [see Adverse Reactions (6)] . 5.4 Cardiac Function Abnormalities In both acromegalic and carcinoid syndrome patients, bradycardia, arrhythmias and conduction abnormalities have been reported during octreotide therapy. Other electrocardiogram (ECG) changes were observed, such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Dose adjustments in drugs, such as beta-blockers that have bradycardic effects may be necessary. In one acromegalic patient with severe congestive heart failure (CHF), initiation of Sandostatin Injection-therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge [see Adverse Reactions (6)] . 5.5 Steatorrhea and Malabsorption of Dietary Fats New onset steatorrhea, stool discoloration and loose stool have been reported in patients receiving somatostatin analogs, including SANDOSTATIN LAR DEPOT. 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 SANDOSTATIN LAR DEPOT, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly. 5.6 Changes in Vitamin B12 Levels Depressed vitamin B 12 levels and abnormal Schilling tests have been observed in some patients receiving octreotide therapy, and monitoring of vitamin B 12 levels is recommended during therapy with SANDOSTATIN LAR DEPOT. 5.7 Changes in Zinc Levels Octreotide has been investigated for the reduction of excessive fluid loss from the GI tract in patients with conditions producing such a loss. If such patients are receiving total parenteral nutrition (TPN), serum zinc may rise excessively when the fluid loss is reversed. Patients on TPN and octreotide should have periodic monitoring of zinc levels. 5.8 Monitoring: Laboratory Tests Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy [see Dosage and Administration (2.1, 2.2)] . Acromegaly: Growth Hormone, IGF-1 (somatomedin C) Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P VIPoma: VIP (plasma vasoactive intestinal peptide) baseline and periodic total and/or free T 4 measurements should be performed during chronic therapy 5.9 Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.1)] .

5.9 Drug Interactions Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine [see Drug Interactions (7.1)] . 7 DRUG INTERACTIONS The following drugs require monitoring and possible dose adjustment when used with SANDOSTATIN LAR DEPOT: Cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine ( 7 ) Lutetium Lu 177 Dotatate Injection: Discontinue SANDOSTATIN LAR DEPOT at least 4 weeks prior to each lutetium Lu 177 dotatate dose ( 7.6 ) 7.1 Cyclosporine Concomitant administration of octreotide injection with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. 7.2 Insulin and Oral Hypoglycemic Drugs Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when SANDOSTATIN LAR DEPOT treatment is initiated and when the dose is altered and anti-diabetic treatment should be adjusted accordingly. 7.3 Bromocriptine Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. 7.4 Other Concomitant Drug Therapy Concomitant administration of bradycardia-inducing drugs (e.g., beta-blockers) may have an additive effect on the reduction of heart rate associated with octreotide. Dose adjustments of concomitant medication may be necessary. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. 7.5 Drug Metabolism Interactions Limited published data indicate that somatostatin analogs may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. 7.6 Lutetium Lu 177 Dotatate Injection Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue SANDOSTATIN LAR DEPOT at least 4 weeks prior to each lutetium Lu 177 dotatate dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.1)] Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.2)] Thyroid Function Abnormalities [see Warnings and Precautions (5.3)] Cardiac Function Abnormalities [see Warnings and Precautions (5.4)] Steatorrhea and Malabsorption of Dietary Fats [see Warnings and Precautions (5.5)] Changes in Vitamin B12 Levels [see Warnings and Precautions (5.6)] Changes in Zinc Levels [see Warnings and Precautions (5.7)] Monitoring: Laboratory Tests [see Warnings and Precautions (5.8)] Drug Interactions [see Warnings and Precautions (5.9)] The most common adverse reactions, occurring in ≥ 20% of patients are: Acromegaly: diarrhea, cholelithiasis, abdominal pain, flatulence ( 6.1 ) Carcinoid Syndrome: back pain, fatigue, headache, abdominal pain, nausea, dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice. Acromegaly The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly has been evaluated in three Phase 3 studies in 261 patients, including 209 exposed for 48 weeks and 96 exposed for greater than 108 weeks. SANDOSTATIN LAR DEPOT was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous Sandostatin Injection were switched to the LAR formulation followed by an open-label extension. The population age range was 14 to 81 years old and 53% were female. Approximately 35% of these acromegaly patients had not been treated with surgery and/or radiation. Most patients received a starting dose of 20 mg every 4 weeks intramuscularly. Dose was up or down titrated based on efficacy and tolerability to a final dose between 10 mg to 60 mg every 4 weeks. Table 1 below reflects adverse events from these studies regardless of presumed causality to study drug. Table 1. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in the Phase 3 Studies Abbreviation: AEs, adverse events. WHO Preferred Term Phase 3 Studies (Pooled) Number (%) of Subjects with AEs 10 mg/20 mg/30 mg (n = 261) n (%) Diarrhea 93 (35.6) Abdominal Pain 75 (28.7) Flatulence 66 (25.3) Influenza-Like Symptoms 52 (19.9) Constipation 46 (17.6) Headache 40 (15.3) Anemia 40 (15.3) Injection-Site Pain 36 (13.8) Cholelithiasis 35 (13.4) Hypertension 33 (12.6) Dizziness 30 (11.5) Fatigue 29 (11.1) The safety of SANDOSTATIN LAR DEPOT in the treatment of acromegaly was also evaluated in a postmarketing randomized Phase 4 study. One-hundred four (104) patients were randomized to either pituitary surgery or 20 mg of SANDOSTATIN LAR DEPOT. All the patients were treatment naïve ( ‘de novo’ ). Crossover was allowed according to treatment response and a total of 76 patients were exposed to Sandostatin LAR. Approximately half of the patients initially randomized to SANDOSTATIN LAR DEPOT were exposed to SANDOSTATIN LAR DEPOT up to 1 year. The population age range was between 20 to 76 years old, 45% were female, 93% were Caucasian, and 1% Black. The majority of these patients were exposed to 30 mg every 4 weeks. Table 2 below reflects the adverse events occurring in this study regardless of presumed causality to study drug. Table 2. Adverse Events Occurring in ≥ 10% of Acromegalic Patients in Phase 4 Study WHO Preferred Term Phase 4 Study SANDOSTATIN LAR DEPOT N = 76 n (%) Phase 4 Study Surgery N = 64 n (%) Diarrhea 36 (47.4) 2 (3.1) Cholelithiasis 29 (38.2) 3 (4.7) Abdominal Pain 19 (25.0) 2 (3.1) Nausea 12 (15.8) 5 (7.8) Alopecia 10 (13.2) 5 (7.8) Injection-Site Pain 9 (11.8) 0 Abdominal Pain Upper 8 (10.5) 0 Headache 8 (10.5) 6 (9.4) Epistaxis 0 7 (10.9) Gallbladder Abnormalities Single doses of Sandostatin Injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with Sandostatin Injection (primarily patients with acromegaly or psoriasis) in patients who had not previously received octreotide acetate, the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin Injection for 12 months or longer was 52%. The incidence of gallbladder abnormalities did not appear to be related to age, sex, or dose but was related to duration of exposure. In clinical trials, 52% of acromegalic patients, most of whom received SANDOSTATIN LAR DEPOT for 12 months or longer, developed new biliary abnormalities including gallstones, microlithiasis, sediment, sludge, and dilatation. The incidence of new cholelithiasis was 22%, of which 7% were microstones. Across all trials, a few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during octreotide therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin Injection therapy and died. Despite the high incidence of new gallstones in patients receiving octreotide acetate, 1% of patients developed acute symptoms requiring cholecystectomy. Glucose Metabolism - Hypoglycemia/Hyperglycemia In acromegaly patients treated with either Sandostatin Injection or SANDOSTATIN LAR DEPOT, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions (5.2)] . Hypothyroidism In acromegaly patients receiving Sandostatin Injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin Injection. In acromegalic patients treated with SANDOSTATIN LAR DEPOT, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving SANDOSTATIN LAR DEPOT required initiation of thyroid hormone replacement therapy [see Warnings and Precautions (5.3)] . Cardiac In acromegalic patients, sinus bradycardia (< 50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin Injection-therapy. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4)] . Gastrointestinal The most common symptoms are gastrointestinal. The overall incidence of the most frequent of these symptoms in clinical trials of acromegalic patients treated for approximately 1 to 4 years is shown in Table 3. Table 3. Number (%) of Acromegalic Patients With Common GI Adverse Events Adverse Event Sandostatin Injection S.C. Three Times Daily n = 114 SANDOSTATIN LAR DEPOT Every 28 Days n = 261 n % n % Diarrhea 66 (57.9) 95 (36.4) Abdominal Pain or Discomfort 50 (43.9) 76 (29.1) Nausea 34 (29.8) 27 (10.3) Flatulence 15 (13.2) 67 (25.7) Constipation 10 (8.8) 49 (18.8) Vomiting 5 (4.4) 17 (6.5) Only 2.6% of the patients on Sandostatin Injection in US clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving SANDOSTATIN LAR DEPOT discontinued therapy for a GI event. In patients receiving SANDOSTATIN LAR DEPOT, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with SANDOSTATIN LAR DEPOT. Thereafter, new cases of these events were uncommon. The vast majority of these events were mild-to-moderate in severity. In rare instances, gastrointestinal adverse effects may resemble acute intestinal obstruction, with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding. Dyspepsia, steatorrhea, discoloration of feces, and tenesmus were reported in 4% to 6% of patients. In a clinical trial of carcinoid syndrome, nausea, abdominal pain, and flatulence were reported in 27% to 38% and constipation or vomiting in 15% to 21% of patients treated with SANDOSTATIN LAR DEPOT. Diarrhea was reported as an adverse event in 14% of patients, but since most of the patients had diarrhea as a symptom of carcinoid syndrome, it is difficult to assess the actual incidence of drug-related diarrhea. Pain at the Injection Site Pain on injection, which is generally mild-to-moderate, and short-lived (usually about 1 hour) is dose related, being reported by 2%, 9%, and 11% of acromegalic patients receiving doses of 10 mg, 20 mg, and 30 mg, respectively, of SANDOSTATIN LAR DEPOT. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20%-25% at a 10-mg dose and about 30%-50% at the 20-mg and 30-mg dose. Antibodies to Octreotide Studies to date have shown that antibodies to octreotide develop in up to 25% of patients treated with octreotide acetate. These antibodies do not influence the degree of efficacy response to octreotide; however, in two acromegalic patients who received Sandostatin Injection, the duration of GH suppression following each injection was about twice as long as in patients without antibodies. It has not been determined whether octreotide antibodies will also prolong the duration of GH suppression in patients being treated with SANDOSTATIN LAR DEPOT. Carcinoid and VIPomas The safety of SANDOSTATIN LAR DEPOT in the treatment of carcinoid tumors and VIPomas has been evaluated in one Phase 3 study. Study 1 randomized 93 patients with carcinoid syndrome to SANDOSTATIN LAR DEPOT 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label Sandostatin Injection subcutaneously. The population age range was between 25 to 78 years old and 44% were female, 95% were Caucasian and 3% Black. All the patients had symptom control on their previous Sandostatin subcutaneous treatment. Eighty (80) patients finished the initial 24 weeks of Sandostatin exposure in Study 1. In Study 1, comparable numbers of patients were randomized to each dose. Table 4 below reflects the adverse events occurring in ≥ 15% of patients regardless of presumed causality to study drug. Table 4. Adverse Events Occurring in ≥ 15% of Carcinoid Tumor and VIPoma Patients in Study 1 Number (%) of Subjects With AEs (n = 93) WHO Preferred Term S.C. N = 26 10 mg N = 22 20 mg N = 20 30 mg N = 25 Abdominal Pain 8 (30.8) 8 (35.4) 2 (10.0) 5 (20.0) Arthropathy 5 (19.2) 2 (9.1) 3 (15.0) 2 (8.0) Back Pain 7 (26.9) 6 (27.3) 2 (10.0) 2 (8.0) Dizziness 4 (15.4) 4 (18.2) 4 (20.0) 5 (20.0) Fatigue 3 (11.5) 7 (31.8) 2 (10.0) 2 (8.0) Flatulence 3 (11.5) 2 (9.1) 2 (10.0) 4 (16.0) Generalized Pain 4 (15.4) 2 (9.1) 3 (15.0) 1 (4.0) Headache 5 (19.2) 4 (18.2) 6 (30.0) 4 (16.0) Musculoskeletal Pain 4 (15.4) 0 1 (5.0) 0 Myalgia 0 4 (18.2) 1 (5.0) 1 (4.0) Nausea 8 (30.8) 9 (40.9) 6 (30.0) 6 (24.0) Pruritus 0 4 (18.2) 0 0 Rash 1 (3.8) 0 3 (15.0) 0 Sinusitis 4 (15.4) 0 1 (5.0) 3 (12.0) URTI 6 (23.1) 4 (18.2) 2 (10.0) 3 (12.0) Vomiting 3 (11.5) 0 0 4 (16.0) Gallbladder Abnormalities In clinical trials, 62% of malignant carcinoid patients, who received SANDOSTATIN LAR DEPOT for up to 18 months, developed new biliary abnormalities including jaundice, gallstones, sludge, and dilatation. New gallstones occurred in a total of 24% of patients. Glucose Metabolism - Hypoglycemia/Hyperglycemia In carcinoid patients, hypoglycemia occurred in 4% and hyperglycemia in 27% of patients treated with SANDOSTATIN LAR DEPOT [see Warnings and Precautions (5.2)] . Hypothyroidism In carcinoid patients, hypothyroidism has only been reported in isolated patients and goiter has not been reported [see Warnings and Precautions (5.3)] . Cardiac Electrocardiograms were performed only in carcinoid patients receiving SANDOSTATIN LAR DEPOT. In carcinoid syndrome patients, sinus bradycardia developed in 19%, conduction abnormalities occurred in 9%, and arrhythmias developed in 3%. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease [see Warnings and Precautions (5.4)] . Other Clinical Studies Adverse Events Other clinically significant adverse events (relationship to drug not established) in acromegalic and/or carcinoid syndrome patients receiving SANDOSTATIN LAR DEPOT were malignant hyperpyrexia, cerebral vascular disorder, rectal bleeding, ascites, pulmonary embolism, pneumonia, and pleural effusion. 6.2 Postmarketing Experience The following adverse reactions have been identified during the postapproval use of SANDOSTATIN LAR DEPOT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic: pancytopenia, thrombocytopenia Cardiac: myocardial infarction, cardiac arrest, atrial fibrillation Ear and labyrinth: deafness Endocrine: diabetes insipidus, adrenal insufficiency in patients 18 months of age and under, pituitary apoplexy Eye: glaucoma, visual field defect, scotoma, retinal vein thrombosis Gastrointestinal: intestinal obstruction, peptic/gastric ulcer, abdomen enlarged, pancreatic exocrine insufficiency General and administration site: generalized edema, facial edema Hepatobiliary: gallbladder polyp, fatty liver, hepatitis Immune: anaphylactoid reactions including anaphylactic shock Infections and infestations: appendicitis Laboratory abnormalities: increased liver enzymes, CK increased, creatinine increased Metabolism and nutrition: diabetes mellitus Musculoskeletal: arthritis, joint effusion, Raynaud’s syndrome Nervous system: convulsions, aneurysm, intracranial hemorrhage, hemiparesis, paresis, suicide attempt, paranoia, migraines, Bell’s palsy, aphasia Renal and urinary: renal failure, renal insufficiency Reproductive and breast: gynecomastia, galactorrhea, libido decrease, breast carcinoma Respiratory: status asthmaticus, pulmonary hypertension, pulmonary nodule, pneumothorax aggravated Skin and subcutaneous tissue: urticaria, cellulitis, petechiae Vascular: orthostatic hypotension, hematuria, gastrointestinal hemorrhage, arterial thrombosis of the arm

8.1 Pregnancy Risk Summary The limited data with SANDOSTATIN LAR DEPOT in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, no adverse developmental effects were observed with intravenous administration of octreotide to pregnant rats and rabbits during organogenesis at doses 7- and 13-times, respectively the maximum recommended human dose (MRHD) of 1.5 mg/day based on body surface area (BSA). Transient growth retardation, with no impact on postnatal development, was observed in rat offspring from a pre- and post-natal study of octreotide at intravenous doses below the MRHD based on BSA ( 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% to 4% and 15% to 20%, respectively. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received intravenous doses of octreotide up to 1 mg/kg/day during the period of organogenesis. A slight reduction in body weight gain was noted in pregnant rats at 0.1 and 1 mg/kg/day. There were no maternal effects in rabbits or embryo-fetal effects in either species up to the maximum dose tested. At 1 mg/kg/day in rats and rabbits, the dose multiple was approximately 7- and 13-times, respectively, at the highest recommended human dose of 1.5 mg/day based on BSA. In a pre- and post-natal development rat study at intravenous doses of 0.02-1 mg/kg/day, a transient growth retardation of the offspring was observed at all doses which was possibly a consequence of growth hormone inhibition by octreotide. The doses attributed to the delayed growth are below the human dose of 1.5 mg/day, based on BSA.