OCTREOTIDE ACETATE

Octreotide is the acetate salt of a cyclic octapeptide. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin. Octreotide is known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxy-methyl) propyl]-, cyclic (2→7)-disulfide; [R-(R*,R*)]. The molecular weight of octreotide is 1019.3 g/mol (free peptide, C 49 H 66 N 10 O 10 S 2 ) and its amino acid sequence is: Octreotide acetate for injectable suspension is available in a single-dose vial containing the sterile drug product, which when mixed with diluent, becomes a suspension that is given as a monthly intragluteal injection. The octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability. Octreotide acetate for injectable suspension is available as: sterile 8-mL single-dose vials in 3 strengths delivering 10 mg, 20 mg, or 30 mg octreotide-free peptide. Each single-dose vial of octreotide acetate for injectable suspension delivers: Name of Ingredient 10 mg 20 mg 30 mg octreotide acetate, USP 11.2 mg * 22.4 mg * 33.6 mg * D,L-lactic and glycolic acids copolymer 188.8 mg 377.6 mg 566.4 mg mannitol 41.0 mg 81.9 mg 122.9 mg *Equivalent to 10 mg, 20 mg, or 30 mg octreotide, respectively. Each prefilled syringe of diluent contains: carboxymethylcellulose sodium 14 mg mannitol 12 mg poloxamer 188 4 mg water for injection q.s. to 2 mL 1

Octreotide acetate for injectable suspension 10 mg, 20 mg, and 30 mg is indicated in patients in whom initial treatment with octreotide acetate injection has been shown to be effective and tolerated. Octreotide acetate for injectable suspension is a somatostatin analogue indicated for: Treatment in patients who have responded to and tolerated octreotide acetate 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 octreotide acetate injection and octreotide acetate for injectable suspension on tumor size, rate of growth and development of metastases, has not been determined.

Octreotide acetate for injectable suspension should be administered by a trained healthcare provider. It is important to closely follow the mixing instructions included in the packaging. Octreotide acetate for injectable suspension must be administered immediately after mixing. Do not directly inject diluent without preparing suspension. The recommended needle size for administration of octreotide acetate for injectable suspension 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. Octreotide acetate for injectable suspension should be administered intramuscularly (IM) in the gluteal region at 4-week intervals. Administration of octreotide acetate for injectable suspension 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. Octreotide acetate for injectable suspension should never be administered intravenously or subcutaneously. The following dosage regimens are recommended. Patients Not Currently Receiving Octreotide Acetate Injection Subcutaneously: Acromegaly: 50 mcg three times daily octreotide acetate injection subcutaneously for 2 weeks followed by octreotide acetate for injectable suspension 20 mg intragluteally every 4 weeks for 3 months ( 2.1 ) Carcinoid Tumors and VIPomas: Octreotide acetate injection subcutaneously 100 mcg/day to 600 mcg/day in 2 to 4 divided doses for 2 weeks followed by octreotide acetate for injectable suspension 20 mg every 4 weeks for 2 months ( 2.2 ) Patients Currently Receiving Octreotide Acetate 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 octreotide acetate 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 octreotide acetate 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 octreotide acetate for injectable suspension in the dosage scheme described below (Patients Currently Receiving Octreotide Acetate Injection). Patients Currently Receiving Octreotide Acetate Injection Patients currently receiving octreotide acetate injection can be switched directly to octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension dosage at 20 mg every 4 weeks GH > 2.5 ng/mL, IGF-1 elevated, and/or clinical symptoms uncontrolled, increase octreotide acetate for injectable suspension dosage to 30 mg every 4 weeks GH ≤ 1 ng/mL, IGF-1 normal, and clinical symptoms controlled, reduce octreotide acetate for injectable suspension 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, octreotide acetate for injectable suspension should be withdrawn yearly for approximately 8 weeks to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide acetate for injectable suspension 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 octreotide acetate injection given subcutaneously. The suggested daily dosage for carcinoid tumors during the first 2 weeks of therapy ranges from 100 mcg/day 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 mcg to 300 mcg in 2 to 4 divided doses (range, 150 mcg to 750 mcg); dosage may be adjusted on an individual basis to control symptoms but usually doses above 450 mcg/day are not required. Octreotide acetate 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 octreotide acetate for injectable suspension in the dosage regimen as described below (Patients Currently Receiving Octreotide Acetate Injection). Patients Currently Receiving Octreotide Acetate Injection Patients currently receiving octreotide acetate injection can be switched to octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension, carcinoid tumor and VIPoma patients should continue to receive octreotide acetate 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 octreotide acetate for injectable suspension 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 octreotide acetate injection or octreotide acetate for injectable suspension). During these periods, they may be given octreotide acetate injection subcutaneously for a few days at the dosage they were receiving prior to switching to octreotide acetate for injectable suspension. When symptoms are again controlled, the octreotide acetate 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 )] .

None. None ( 4 )

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

The following drugs require monitoring and possible dose adjustment when used with octreotide acetate for injectable suspension: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine ( 7 ) Lutetium Lu 177 Dotatate Injection: Discontinue octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension 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 octreotide acetate for injectable suspension at least 4 weeks prior to each lutetium Lu 177 dotatate dose.