Octreotide Acetate

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 Octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension [see Adverse Reactions ( 6 )] . Patients should be monitored periodically. If complications of cholelithiasis are suspected, discontinue octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension 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 octreotide acetate 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 octreotide acetate for injectable suspension. 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 octreotide acetate for injectable suspension, evaluate patients for potential pancreatic exocrine insufficiency and manage accordingly. 5.6 Changes in Vitamin B 12 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 octreotide acetate for injectable suspension. 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 )] .

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 B 12 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 Teva at 1-888-838-2872 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 octreotide acetate for injectable suspension 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. Octreotide acetate for injectable suspension was studied primarily in a double-blind, cross-over manner. Patients on subcutaneous octreotide acetate injection were switched to the octreotide acetate for injectable suspension 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 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) Abbreviation: AEs, adverse events. The safety of octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension. All the patients were treatment naïve (‘ de novo ’). Crossover was allowed according to treatment response and a total of 76 patients were exposed to octreotide acetate for injectable suspension. Approximately half of the patients initially randomized to octreotide acetate for injectable suspension were exposed to octreotide acetate for injectable suspension 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 Octreotide Acetate for Injectable Suspension Phase 4 Study Surgery N = 76 N = 64 n (%) 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 octreotide acetate injection have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials with octreotide acetate 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 octreotide acetate 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 octreotide acetate for injectable suspension 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 octreotide acetate 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 octreotide acetate injection or octreotide acetate for injectable suspension, hypoglycemia occurred in approximately 2% and hyperglycemia in approximately 15% of patients [see Warnings and Precautions ( 5.2 )] . Hypothyroidism In acromegaly patients receiving octreotide acetate injection, 12% developed biochemical hypothyroidism, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving octreotide acetate injection. In acromegalic patients treated with octreotide acetate for injectable suspension, hypothyroidism was reported as an adverse event in 2% and goiter in 2%. Two patients receiving octreotide acetate for injectable suspension 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 octreotide acetate 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 Octreotide Acetate Injection S.C. Three Times Daily n = 114 Octreotide Acetate for Injectable Suspension 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 octreotide acetate injection in U.S. clinical trials discontinued therapy due to these symptoms. No acromegalic patient receiving octreotide acetate for injectable suspension discontinued therapy for a GI event. In patients receiving octreotide acetate for injectable suspension, the incidence of diarrhea was dose related. Diarrhea, abdominal pain, and nausea developed primarily during the first month of treatment with octreotide acetate for injectable suspension. 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 octreotide acetate for injectable suspension. 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 octreotide acetate for injectable suspension. In carcinoid patients, where a diary was kept, pain at the injection site was reported by about 20% to 25% at a 10-mg dose and about 30% to 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 octreotide acetate 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 octreotide acetate for injectable suspension. Carcinoid and VIPomas The safety of octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension 10 mg, 20 mg, or 30 mg in a blind fashion or to open-label octreotide acetate 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 octreotide acetate subcutaneous treatment. Eighty (80) patients finished the initial 24 weeks of octreotide acetate 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 octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension [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 octreotide acetate for injectable suspension. 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 octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension. 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

<table><caption>Table 1. Adverse Events Occurring in &#x2265; 10% of Acromegalic Patients in the Phase 3 Studies</caption><col width="225.9pt"/><col width="252.9pt"/><tbody><tr><td styleCode=" Toprule"><paragraph><content styleCode="bold">WHO Preferred Term</content></paragraph></td><td align="center" styleCode=" Toprule"><paragraph><content styleCode="bold">Phase 3 Studies (Pooled) </content><content styleCode="bold">Number (%) of Subjects with AEs </content><content styleCode="bold">10 mg/20 mg/30 mg </content><content styleCode="bold">(n = 261) </content><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode=" Toprule"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode=" Toprule"><paragraph>93 (35.6)</paragraph></td></tr><tr><td><paragraph>Abdominal Pain</paragraph></td><td align="center"><paragraph>75 (28.7)</paragraph></td></tr><tr><td><paragraph>Flatulence</paragraph></td><td align="center"><paragraph>66 (25.3)</paragraph></td></tr><tr><td><paragraph>Influenza-Like Symptoms</paragraph></td><td align="center"><paragraph>52 (19.9)</paragraph></td></tr><tr><td><paragraph>Constipation</paragraph></td><td align="center"><paragraph>46 (17.6)</paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td align="center"><paragraph>40 (15.3)</paragraph></td></tr><tr><td><paragraph>Anemia</paragraph></td><td align="center"><paragraph>40 (15.3)</paragraph></td></tr><tr><td><paragraph>Injection-Site Pain</paragraph></td><td align="center"><paragraph>36 (13.8)</paragraph></td></tr><tr><td><paragraph>Cholelithiasis</paragraph></td><td align="center"><paragraph>35 (13.4)</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td align="center"><paragraph>33 (12.6)</paragraph></td></tr><tr><td><paragraph>Dizziness</paragraph></td><td align="center"><paragraph>30 (11.5)</paragraph></td></tr><tr><td styleCode=" Botrule"><paragraph>Fatigue</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>29 (11.1)</paragraph></td></tr><tr><td colspan="2"> Abbreviation: AEs, adverse events.</td></tr></tbody></table>

<table><caption>Table 2. Adverse Events Occurring in &#x2265; 10% of Acromegalic Patients in Phase 4 Study</caption><col width="159.6pt"/><col width="159.6pt"/><col width="159.6pt"/><tbody><tr><td styleCode=" Toprule"><paragraph><content styleCode="bold">WHO Preferred Term</content></paragraph></td><td align="center" styleCode=" Toprule"><paragraph><content styleCode="bold">Phase 4 Study </content><content styleCode="bold">Octreotide Acetate for Injectable Suspension</content></paragraph></td><td align="center" styleCode=" Toprule"><paragraph><content styleCode="bold">Phase 4 Study </content><content styleCode="bold">Surgery</content></paragraph></td></tr><tr><td/><td align="center"><paragraph><content styleCode="bold">N = 76</content></paragraph></td><td align="center"><paragraph><content styleCode="bold">N = 64</content></paragraph></td></tr><tr><td styleCode=" Botrule"/><td align="center" styleCode=" Botrule"><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode=" Botrule"><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td align="center"><paragraph>36 (47.4)</paragraph></td><td align="center"><paragraph>2 (3.1)</paragraph></td></tr><tr><td><paragraph>Cholelithiasis</paragraph></td><td align="center"><paragraph>29 (38.2)</paragraph></td><td align="center"><paragraph>3 (4.7)</paragraph></td></tr><tr><td><paragraph>Abdominal Pain</paragraph></td><td align="center"><paragraph>19 (25.0)</paragraph></td><td align="center"><paragraph>2 (3.1)</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td align="center"><paragraph>12 (15.8)</paragraph></td><td align="center"><paragraph>5 (7.8)</paragraph></td></tr><tr><td><paragraph>Alopecia</paragraph></td><td align="center"><paragraph>10 (13.2)</paragraph></td><td align="center"><paragraph>5 (7.8)</paragraph></td></tr><tr><td><paragraph>Injection-Site Pain</paragraph></td><td align="center"><paragraph>9 (11.8)</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td><paragraph>Abdominal Pain Upper</paragraph></td><td align="center"><paragraph>8 (10.5)</paragraph></td><td align="center"><paragraph>0</paragraph></td></tr><tr><td><paragraph>Headache</paragraph></td><td align="center"><paragraph>8 (10.5)</paragraph></td><td align="center"><paragraph>6 (9.4)</paragraph></td></tr><tr><td styleCode=" Botrule"><paragraph>Epistaxis</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>7 (10.9)</paragraph></td></tr></tbody></table>

<table><caption>Table 3. Number (%) of Acromegalic Patients with Common GI Adverse Events</caption><col/><col/><col/><col/><col/><tbody><tr><td styleCode=" Toprule"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" colspan="2" styleCode=" Toprule"><paragraph><content styleCode="bold">Octreotide Acetate </content><content styleCode="bold">Injection S.C. </content><content styleCode="bold">Three Times Daily </content><content styleCode="bold">n = 114</content></paragraph></td><td align="center" colspan="2" styleCode=" Toprule"><paragraph><content styleCode="bold">Octreotide Acetate for Injectable Suspension </content><content styleCode="bold">Every 28 Days </content><content styleCode="bold">n = 261</content></paragraph></td></tr><tr><td styleCode=" Toprule"/><td align="center" styleCode=" Toprule"><paragraph>n</paragraph></td><td align="center" styleCode=" Toprule"><paragraph>%</paragraph></td><td align="center" styleCode=" Toprule"><paragraph>n</paragraph></td><td align="center" styleCode=" Toprule"><paragraph>%</paragraph></td></tr><tr><td><paragraph>Diarrhea</paragraph></td><td align="center"><paragraph>66</paragraph></td><td align="center"><paragraph>(57.9)</paragraph></td><td align="center"><paragraph>95</paragraph></td><td align="center"><paragraph>(36.4)</paragraph></td></tr><tr><td><paragraph>Abdominal Pain or Discomfort</paragraph></td><td align="center"><paragraph>50</paragraph></td><td align="center"><paragraph>(43.9)</paragraph></td><td align="center"><paragraph>76</paragraph></td><td align="center"><paragraph>(29.1)</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td align="center"><paragraph>34</paragraph></td><td align="center"><paragraph>(29.8)</paragraph></td><td align="center"><paragraph>27</paragraph></td><td align="center"><paragraph>(10.3)</paragraph></td></tr><tr><td><paragraph>Flatulence</paragraph></td><td align="center"><paragraph>15</paragraph></td><td align="center"><paragraph>(13.2)</paragraph></td><td align="center"><paragraph>67</paragraph></td><td align="center"><paragraph>(25.7)</paragraph></td></tr><tr><td><paragraph>Constipation</paragraph></td><td align="center"><paragraph>10</paragraph></td><td align="center"><paragraph>(8.8)</paragraph></td><td align="center"><paragraph>49</paragraph></td><td align="center"><paragraph>(18.8)</paragraph></td></tr><tr><td styleCode=" Botrule"><paragraph>Vomiting</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>5</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>(4.4)</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>17</paragraph></td><td align="center" styleCode=" Botrule"><paragraph>(6.5)</paragraph></td></tr></tbody></table>