These Highlights Do Not Include All The Information Needed To Use Octreotide Acetate Injection Safely And Effectively. See Full Prescribing Information For Octreotide Acetate Injection.

Complete Atrioventricular Block

Patients who receive octreotide acetate intravenously may be at increased risk for higher degree atrioventricular blocks. In post marketing reports, complete atrioventricular block was reported in patients receiving IV octreotide acetate during surgical procedures. In the majority of patients, octreotide acetate was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving octreotide acetate for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate intravenously.

Storage Conditions

Store refrigerated between 2° and 8°C (36° and 46°F). At room temperature (20° to 30°C or 70° to 86°F), Octreotide Acetate Injection is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially.

Single-Dose Vials—should be opened just prior to administration and the unused portion discarded.

Multi-Dose Vials—should be discarded within 14 days after initial use.

Protect from light. Retain in carton until time of use.

Dispose of unused product or waste properly. Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours.

Sterile, Nonpyrogenic.

The container closure is not made with natural rubber latex.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-466-05

Rx only

Octreotide Acetate Injection

1,000 mcg per 5 mL

(200 mcg per mL)

5 mL Multi-Dose Vial

For Subcutaneous or Intravenous Use

A limited number of accidental overdoses of octreotide acetate in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss.

If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222.

Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.

Octreotide Acetate Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered acetate solution with a pH range 3.9 to 4.5 for administration by deep subcutaneous (intrafat) or intravenous (IV) injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl) propyl]-,cyclic (2 → 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.

Octreotide Acetate Injection is available as sterile 1 mL single-dose vials in 3 strengths, containing 50 mcg, 100 mcg, or 500 mcg octreotide acetate, USP. Each mL of the single-dose vial also contains sodium chloride, USP (7 mg), glacial acetic acid, USP (2 mg), sodium acetate trihydrate, USP (2 mg), and water for injection, USP (quantity sufficient to 1 mL).

Octreotide Acetate Injection is also available as sterile 5 mL multi-dose vials in 2 strengths, containing 200 mcg, or 1,000 mcg per mL of octreotide acetate, USP. Each mL of the multi-dose vial also contains sodium chloride, USP (7 mg), glacial acetic acid, USP (2 mg), sodium acetate trihydrate, USP (2 mg), phenol, USP (5 mg), and water for injection, USP (quantity sufficient to 1 mL).

The molecular weight of octreotide acetate is 1,019.3 g/mol (free peptide, C₄₉H₆₆N₁₀O₁₀S₂) and its amino acid sequence is:

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 acetate with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Safety and efficacy of octreotide acetate in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of octreotide acetate using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m² in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m² in saline control-treated subjects.

Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month.

Clinical studies of octreotide acetate 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.

Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients.

Sensitivity to this drug or any of its components.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Complete Atrioventricular Block [see Warnings and Precautions (5.1)]
• Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.2)]
• Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.3)]
• Thyroid 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)]

• The following drugs require monitoring and possible dose adjustment when used with octreotide acetate: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. (7)
• Lutetium Lu 177 Dotatate Injection: Discontinue octreotide acetate at least 24 hours prior to each lutetium Lu 177 dotatate dose. (7.6)

Octreotide Acetate Injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

In patients with severe renal failure requiring dialysis, the half-life of octreotide acetate may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)].

Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly.

Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)].

Octreotide suppresses secretion of TSH.

Octreotide Acetate Injection is a somatostatin analogue indicated:

• Acromegaly: To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. (1.1)
• Carcinoid Tumors: For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. (1.2)
• Vasoactive Intestinal Peptide Tumors (VIPomas): For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. (1.3)

Limitations of Use

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects. (1.4)

Octreotide acetate exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide.

By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea).

• Cardiac Function Abnormalities: Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving octreotide acetate intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. (5.1)
• Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected. (5.2)
• Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. (5.3)
• Thyroid Function: Hypothyroidism may occur. Monitor thyroid levels periodically. (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)

• Octreotide acetate injection may be administered subcutaneously or intravenously. (2.1)
• Acromegaly: Recommended initial octreotide acetate injection dosage is 50 mcg three times daily during the initial 2 weeks of therapy. Maintenance dose 100 mcg to 500 mcg three times daily. (2.2)
• Carcinoid Tumors: Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.3)
• VIPomas: Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.4)

Octreotide Acetate Injection is available as 50 mcg per mL, 100 mcg per mL, or 500 mcg per mL of octreotide acetate, USP in single-dose vials and 1,000 mcg per 5 mL (200 mcg per mL) and 5,000 mcg per 5 mL (1,000 mcg per mL) of octreotide acetate, USP in multi-dose vials.

The following adverse reactions have been identified during postapproval use of octreotide acetate. 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.

Hepatobiliary: cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy

Gastrointestinal: intestinal obstruction, pancreatic exocrine insufficiency

Hematologic: thrombocytopenia

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

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 trials of another drug and may not reflect the rates observed in practice.

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. 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.

Depressed vitamin B₁₂ levels and abnormal Schilling's tests have been observed in some patients receiving octreotide acetate therapy, and monitoring of vitamin B₁₂ levels is recommended during octreotide acetate therapy.

Octreotide acetate alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate in 3% and 16% of acromegalic patients, respectively [see Adverse Reactions (6)]. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate therapy was reported in one patient with no history of hyperglycemia.

Monitor glucose levels during octreotide acetate therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly.

Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T₄) is recommended during chronic therapy [see Adverse Reactions (6)].

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.

Octreotide Acetate Injection is available as follows:

• Octreotide acetate injection may be administered subcutaneously or intravenously. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Sites should be rotated in a systematic manner.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Octreotide acetate injection is not compatible in Total Parenteral Nutrition solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.
• Octreotide acetate injection may be diluted in volumes of 50 mL to 200 mL and infused intravenously over 15 to 30 minutes or administered by intravenous (IV) push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus.
• Assess total and/or free T4 levels at baseline and periodically during chronic octreotide acetate injection therapy.

Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue octreotide acetate at least 24 hours prior to each lutetium Lu 177 dotatate dose.

Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when octreotide acetate treatment is initiated or when the dose is altered and anti-diabetic treatment should be adjusted accordingly.

Octreotide Acetate Injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors.

In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)].

Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility.

The recommended initial dosage of octreotide acetate injection is 50 mcg three times daily to be administered subcutaneously. Increase octreotide acetate injection dose based upon GH or IGF-1 levels. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 levels within normal range. Monitor GH or IGF-1 every two weeks after initiating octreotide acetate injection therapy or with dosage change, and to guide titration.

The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced.

Octreotide acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide acetate injection therapy may be resumed.

Octreotide acetate may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide acetate therapy. In clinical trials (primarily patients with acromegaly or psoriasis), 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 for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide acetate therapy and died. If complications of cholelithiasis are suspected, discontinue octreotide acetate and treat appropriately.

Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate.

No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.

Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA.

The recommended daily dosage of octreotide acetate injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in two to four divided doses given subcutaneously (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. Measurement of urinary 5- hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy.

Daily dosages of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required. Measurement of Plasma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy.

Complete Atrioventricular Block

Patients who receive octreotide acetate intravenously may be at increased risk for higher degree atrioventricular blocks. In post marketing reports, complete atrioventricular block was reported in patients receiving IV octreotide acetate during surgical procedures. In the majority of patients, octreotide acetate was given at higher than recommended doses and/or as a continuous IV infusion. The safety of continuous IV infusion has not been established in patients receiving octreotide acetate for the approved indications. Consider cardiac monitoring in patients receiving octreotide acetate intravenously.

Storage Conditions

Store refrigerated between 2° and 8°C (36° and 46°F). At room temperature (20° to 30°C or 70° to 86°F), Octreotide Acetate Injection is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially.

Single-Dose Vials—should be opened just prior to administration and the unused portion discarded.

Multi-Dose Vials—should be discarded within 14 days after initial use.

Protect from light. Retain in carton until time of use.

Dispose of unused product or waste properly. Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours.

Sterile, Nonpyrogenic.

The container closure is not made with natural rubber latex.

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – Vial Label

NDC 25021-466-05

Rx only

Octreotide Acetate Injection

1,000 mcg per 5 mL

(200 mcg per mL)

5 mL Multi-Dose Vial

For Subcutaneous or Intravenous Use

A limited number of accidental overdoses of octreotide acetate in adults have been reported. In adults, the doses ranged from 2,400 to 6,000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1,500 mcg 3 times a day). Adverse events in some patients included arrhythmia, complete atrioventricular block, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss.

If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222.

Octreotide Acetate Injection is indicated to reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses.

Octreotide Acetate Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered acetate solution with a pH range 3.9 to 4.5 for administration by deep subcutaneous (intrafat) or intravenous (IV) injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl) propyl]-,cyclic (2 → 7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.

Octreotide Acetate Injection is available as sterile 1 mL single-dose vials in 3 strengths, containing 50 mcg, 100 mcg, or 500 mcg octreotide acetate, USP. Each mL of the single-dose vial also contains sodium chloride, USP (7 mg), glacial acetic acid, USP (2 mg), sodium acetate trihydrate, USP (2 mg), and water for injection, USP (quantity sufficient to 1 mL).

Octreotide Acetate Injection is also available as sterile 5 mL multi-dose vials in 2 strengths, containing 200 mcg, or 1,000 mcg per mL of octreotide acetate, USP. Each mL of the multi-dose vial also contains sodium chloride, USP (7 mg), glacial acetic acid, USP (2 mg), sodium acetate trihydrate, USP (2 mg), phenol, USP (5 mg), and water for injection, USP (quantity sufficient to 1 mL).

The molecular weight of octreotide acetate is 1,019.3 g/mol (free peptide, C₄₉H₆₆N₁₀O₁₀S₂) and its amino acid sequence is:

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 acetate with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Safety and efficacy of octreotide acetate in the pediatric population have not been demonstrated.

No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of octreotide acetate in pediatric patients under age 6 years. In postmarketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with octreotide acetate use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions.

The efficacy and safety of octreotide acetate using the octreotide acetate for injectable suspension formulation was examined in a single randomized, double-blind, placebo-controlled, 6 month pharmacokinetics study in 60 pediatric patients age 6 to 17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg octreotide acetate for injectable suspension administered by intramuscular (IM) injection every 4 weeks was approximately 3 ng/mL. Steady-state concentrations was achieved after 3 injections of a 40-mg dose. Mean body mass index (BMI) increased 0.1 kg/m² in octreotide acetate for injectable suspension-treated subjects compared to 0.0 kg/m² in saline control-treated subjects.

Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with octreotide acetate for injectable suspension. No unexpected adverse events were observed. However, with octreotide acetate for injectable suspension at 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adult indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where octreotide acetate for injectable suspension was 10 mg to 30 mg once a month.

Clinical studies of octreotide acetate 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.

Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to octreotide acetate were subsequently reported in 3 patients and resulted in prolonged duration of drug action in 2 patients.

Sensitivity to this drug or any of its components.

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Complete Atrioventricular Block [see Warnings and Precautions (5.1)]
• Cholelithiasis and Complications of Cholelithiasis [see Warnings and Precautions (5.2)]
• Hyperglycemia and Hypoglycemia [see Warnings and Precautions (5.3)]
• Thyroid 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)]

• The following drugs require monitoring and possible dose adjustment when used with octreotide acetate: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, and bromocriptine. (7)
• Lutetium Lu 177 Dotatate Injection: Discontinue octreotide acetate at least 24 hours prior to each lutetium Lu 177 dotatate dose. (7.6)

Octreotide Acetate Injection is indicated for treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.

In patients with severe renal failure requiring dialysis, the half-life of octreotide acetate may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)].

Octreotide substantially reduces GH and/or IGF-1 (somatomedin C) levels in patients with acromegaly.

Single doses of octreotide have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials, the incidence of gallstone or biliary sludge formation was markedly increased [see Warnings and Precautions (5.2)].

Octreotide suppresses secretion of TSH.

Octreotide Acetate Injection is a somatostatin analogue indicated:

• Acromegaly: To reduce blood levels of growth hormone (GH) and insulin growth factor-1 (IGF-1; somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. (1.1)
• Carcinoid Tumors: For the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. (1.2)
• Vasoactive Intestinal Peptide Tumors (VIPomas): For the treatment of profuse watery diarrhea associated with VIP-secreting tumors. (1.3)

Limitations of Use

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects. (1.4)

Octreotide acetate exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin, and pancreatic polypeptide.

By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and VIP secreting adenomas (watery diarrhea).

• Cardiac Function Abnormalities: Increased risk for higher degree of atrioventricular blocks. Consider cardiac monitoring in patients receiving octreotide acetate intravenously. Bradycardia, arrhythmias, or conduction abnormalities may occur. Use with caution in at-risk patients. Dosage adjustment of cardiac medications may be necessary. (5.1)
• Cholelithiasis and Complications of Cholelithiasis: Monitor periodically. Discontinue if complications of cholelithiasis are suspected. (5.2)
• Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Glucose monitoring is recommended and anti-diabetic treatment may need adjustment. (5.3)
• Thyroid Function: Hypothyroidism may occur. Monitor thyroid levels periodically. (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)

• Octreotide acetate injection may be administered subcutaneously or intravenously. (2.1)
• Acromegaly: Recommended initial octreotide acetate injection dosage is 50 mcg three times daily during the initial 2 weeks of therapy. Maintenance dose 100 mcg to 500 mcg three times daily. (2.2)
• Carcinoid Tumors: Recommended dosage range of 100 mcg to 600 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.3)
• VIPomas: Recommended dosage range of 200 mcg to 300 mcg daily in two to four divided doses during the initial 2 weeks of therapy. (2.4)

Octreotide Acetate Injection is available as 50 mcg per mL, 100 mcg per mL, or 500 mcg per mL of octreotide acetate, USP in single-dose vials and 1,000 mcg per 5 mL (200 mcg per mL) and 5,000 mcg per 5 mL (1,000 mcg per mL) of octreotide acetate, USP in multi-dose vials.

The following adverse reactions have been identified during postapproval use of octreotide acetate. 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.

Hepatobiliary: cholelithiasis, cholecystitis, cholangitis and pancreatitis, which have sometimes required cholecystectomy

Gastrointestinal: intestinal obstruction, pancreatic exocrine insufficiency

Hematologic: thrombocytopenia

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

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 trials of another drug and may not reflect the rates observed in practice.

Improvement in clinical signs and symptoms, or reduction in tumor size or rate of growth, were not shown in clinical trials performed with Octreotide Acetate Injection; these trials were not optimally designed to detect such effects.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH. 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.

Depressed vitamin B₁₂ levels and abnormal Schilling's tests have been observed in some patients receiving octreotide acetate therapy, and monitoring of vitamin B₁₂ levels is recommended during octreotide acetate therapy.

Octreotide acetate alters the balance between the counter-regulatory hormones, insulin, glucagon and GH, which may result in hypoglycemia or hyperglycemia. The hypoglycemia or hyperglycemia which occurs during octreotide acetate therapy is usually mild but may result in overt diabetes mellitus or necessitate dose changes in insulin or other anti-diabetic agents. Hypoglycemia and hyperglycemia occurred on octreotide acetate in 3% and 16% of acromegalic patients, respectively [see Adverse Reactions (6)]. Severe hyperglycemia, subsequent pneumonia, and death following initiation of octreotide acetate therapy was reported in one patient with no history of hyperglycemia.

Monitor glucose levels during octreotide acetate therapy. Adjust dosing of insulin or other anti-diabetic therapy accordingly.

Octreotide suppresses secretion of thyroid stimulating hormone (TSH), which may result in hypothyroidism. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T₄) is recommended during chronic therapy [see Adverse Reactions (6)].

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.

Octreotide Acetate Injection is available as follows:

• Octreotide acetate injection may be administered subcutaneously or intravenously. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Sites should be rotated in a systematic manner.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Octreotide acetate injection is not compatible in Total Parenteral Nutrition solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.
• Octreotide acetate injection may be diluted in volumes of 50 mL to 200 mL and infused intravenously over 15 to 30 minutes or administered by intravenous (IV) push over 3 minutes. In emergency situations (e.g., carcinoid crisis), it may be given by rapid bolus.
• Assess total and/or free T4 levels at baseline and periodically during chronic octreotide acetate injection therapy.

Octreotide competitively binds to somatostatin receptors and may interfere with the efficacy of lutetium Lu 177 dotatate. Discontinue octreotide acetate at least 24 hours prior to each lutetium Lu 177 dotatate dose.

Octreotide inhibits the secretion of insulin and glucagon. Therefore, blood glucose levels should be monitored when octreotide acetate treatment is initiated or when the dose is altered and anti-diabetic treatment should be adjusted accordingly.

Octreotide Acetate Injection is indicated for the treatment of the profuse watery diarrhea associated with vasoactive intestinal peptide tumors (VIPomas)-secreting tumors.

In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage [see Clinical Pharmacology (12.3)].

Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in GH levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in acromegalic females treated with octreotide may lead to improved fertility.

The recommended initial dosage of octreotide acetate injection is 50 mcg three times daily to be administered subcutaneously. Increase octreotide acetate injection dose based upon GH or IGF-1 levels. The goal is to achieve GH levels less than 5 ng/mL or IGF-1 levels within normal range. Monitor GH or IGF-1 every two weeks after initiating octreotide acetate injection therapy or with dosage change, and to guide titration.

The most common dosage is 100 mcg three times daily, but some patients require up to 500 mcg three times daily for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced.

Octreotide acetate injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If GH or IGF-1 levels increase and signs and symptoms recur, octreotide acetate injection therapy may be resumed.

Octreotide acetate may inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. Acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis have been reported with octreotide acetate therapy. In clinical trials (primarily patients with acromegaly or psoriasis), 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 for 12 months or longer was 52%. Less than 2% of patients treated with octreotide acetate for 1 month or less developed gallstones. One patient developed ascending cholangitis during octreotide acetate therapy and died. If complications of cholelithiasis are suspected, discontinue octreotide acetate and treat appropriately.

Studies in laboratory animals have demonstrated no mutagenic potential of octreotide acetate.

No carcinogenic potential was demonstrated in mice treated subcutaneously for 85 to 99 weeks at doses up to 2,000 mcg/kg/day (8 x the human exposure based on BSA). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection-site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1,250 mcg/kg/day (10 x the human exposure based on BSA) compared to an incidence of 8% to 10% in the vehicle-control groups. The increased incidence of injection-site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection-site tumors in patients treated with octreotide acetate for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1,250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans.

Octreotide did not impair fertility in rats at doses up to 1,000 mcg/kg/day, which represents 7-times the human exposure based on BSA.

The recommended daily dosage of octreotide acetate injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in two to four divided doses given subcutaneously (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. Measurement of urinary 5- hydroxyindole acetic acid, plasma serotonin, plasma Substance P may be useful in monitoring the progress of therapy.

Daily dosages of 200 mcg to 300 mcg in two to four divided doses given subcutaneously are recommended during the initial 2 weeks of therapy (range, 150 mcg to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required. Measurement of Plasma vasoactive intestinal peptide (VIP) may be useful in monitoring the progress of therapy.