OCTREOTIDE ACETATE (Generic for SANDOSTATIN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Octreotide Injection Solution (e.g., Sandostatin)
-For intravenous (IV) or subcutaneous administration only.
-Octreotide injection solution can be allowed to reach room temperature prior to administration. Do not warm artificially.
-Storage: Unopened injection is usually stored at refrigerated temperatures between 36 to 46 degrees F in the outer carton to protect from light. Unopened ampules and vials are stable for 14 days at room temperature if protected from light. Discard any unused portion of an ampule once opened. Discard multiple-dose vials 14 days after initial use.
Intravenous Administration
Octreotide Injection Solution (e.g., Sandostatin)

IV Push
-In emergency situations, octreotide may be administered undiluted by intermittent direct IV injection slowly over 3 minutes.

Intermittent IV Infusion
-Dilute in 50 to 200 mL of 0.9% NaCl Injection or 5% Dextrose Injection; infuse over 15 to 30 minutes.
-Once diluted, the IV infusion solution is stable for 24 hours.

Continuous IV Infusion
-Dilute in 50 to 200 mL of 0.9% NaCl Injection or 5% Dextrose Injection.
-Administer the continuous infusion at the ordered dose rate using a rate-controlled infusion device.
-Once diluted, IV infusions are stable for 24 hours.

Subcutaneous Administration
Octreotide Injection Solution (e.g., Sandostatin)
-Administer subcutaneously undiluted unless the injection dose volume cannot be accurately administered without further dilution with 0.9% NaCl Injection.
-To minimize pain, use smallest injection volume that will deliver the desired dose.
-Rotate subcutaneous injection sites.

The most common adverse effects of octreotide are gastrointestinal. In rare instances, gastrointestinal side effects may resemble acute GI obstruction (e.g., ileus), with progressive abdominal distention, severe epigastric pain, abdominal tenderness, and guarding. Necrotizing enterocolitis (NEC) has been reported in term neonates receiving octreotide therapy for hyperinsulinemic hypoglycemia and chylothorax. More commonly, abdominal pain, diarrhea, and loose stools are reported in adult patients receiving octreotide; consistent adverse reactions have been reported in pediatric literature. Other gastrointestinal effects include nausea, vomiting, flatulence, abnormal stools, steatorrhea, stool discoloration, tenesmus, abdominal distention, appendicitis, hemorrhoids, constipation, gastroparesis, dyspepsia, gastric/peptic ulcer, GI bleeding, and rectal bleeding. In adult patients receiving the depot formulation, events were generally described as mild-to-moderate in severity. Diarrhea was dose-related and, along with abdominal pain and nausea, was uncommon after the first month of treatment. Hepatitis, jaundice, elevated hepatic enzymes, gallbladder polyp, ascites, and fatty liver (steatosis) have also been reported with octreotide use in adult patients; however causality to the drug has not been established. Monitor pediatric patients for excessive fluid losses and electrolyte abnormalities. Neonates and infants should be closely monitored for signs and symptoms of NEC (e.g., abdominal distention, absent bowel sounds, bloody stools, hypotension).

Cholelithiasis and/or biliary sludge frequently develop in patients on chronic octreotide therapy. Octreotide decreases bile secretion, modifies bile composition, and decreases gallbladder motility. The incidence of gallbladder abnormalities and cholelithiasis does not appear to be related to age, sex, or dose but may be influenced by duration of octreotide therapy. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% [27% cholelithiasis (gallstones), 24% sludge without stones, 12% biliary duct dilatation]. In these adult patients, less than 2% of patients treated with octreotide for 1 month or less developed gallstones; however, those on therapy at least 12 months had a 52% incidence rate of developing gallstones or biliary sludge. In patients receiving octreotide, there have been postmarketing reports of cholelithiasis resulting in complications, including cholecystitis, cholangitis, and pancreatitis with some complications requiring cholecystectomy. Gallstones are typically small and asymptomatic; baseline and period ultrasound evaluations are controversial because, in general, asymptomatic cholelithiasis requires no intervention. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during therapy or following its withdrawal. Because octreotide-associated gallstones are cholesterol-rich, oral ursodiol may be effective in patients with biliary symptoms. In a small clinical trial (n = 20), 44% of pediatric patients receiving octreotide (mean age 13.8 +/- 1.2 years) developed gallstone or sludge formation detectable by ultrasound by month 6 of therapy; these patients were treated with oral ursodiol and had complete resolution of gallbladder anomalies at the 12-month ultrasound.

Injection site reaction, including pain, hematoma, and bruising have been reported by adult patients receiving octreotide. Reactions may be route, formulation, and dose-dependent.

Octreotide may cause hypoglycemia or hyperglycemia by altering the balance between the counter-regulatory hormones insulin, glucagon, and growth hormone in the body. Insulin requirements may be reduced in patients with type 1 diabetes mellitus. Conversely, insulin levels may decrease and hyperglycemia may occur in non-diabetics and patients with type 2 diabetes with partially intact insulin reserves. Severe hyperglycemia, subsequent pneumonia, and death following treatment with octreotide was reported in one adult patient with no history of hyperglycemia. Though octreotide is used to increase blood glucose concentrations in patients with congenital hyperinsulinism, it may occasionally aggravate hypoglycemia in these patients. Glycemic effects in adults are usually mild, however pediatric patients should be monitored closely as fluctuations in blood glucose may necessitate the need to alter enteral feedings, dextrose-containing fluids, and/or concomitant medications that influence blood glucose.

Bradycardia is one of the most common adverse effects of octreotide reported in the adult population. Pulmonary hypertension and hypoxemia has been described in a case report of 2 premature neonates with chronic lung disease; pulmonary hypertension has also been reported postmarketing during use of the octreotide depot injection in adult patients. Other cardiovascular effects reported during adult clinical trials include hypertension, cardiac arrhythmias, and conduction abnormalities. ECG changes such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and nonspecific ST-T wave changes have been reported in adult acromegalic and carcinoid syndrome patients; however, the relationship to the drug is not established, as cardiac disease is prevalent in these conditions. Other cardiac effects reported include AV block, myocardial infarction, chest pain (unspecified), shortness of breath, thrombo-phlebitis, ischemia, new or worsening heart failure, hypertensive reaction, palpitations, orthostatic hypotension, sinus tachycardia, cardiac arrest, and atrial fibrillation.

Vitamin B12 deficiency may occur in patients receiving octreotide. In addition, octreotide can cause dietary fat malabsorption. Proper nutrition and adequate weight gain should be assessed in all pediatric patients experiencing steatorrhea, diarrhea, and/or excessive fluid loss from the GI tract; weight loss has rarely been reported in adult patients. In patients receiving total parenteral nutrition (TPN) for excessive fluid loss, serum zinc levels may rise excessively when the fluid loss is reversed. Monitor periodic vitamin B12 levels; zinc levels should be monitored periodically in patients on TPN and octreotide.

Octreotide suppresses the secretion of thyroid-stimulating hormone, which may result in hypothyroidism. Biochemical hypothyroidism (2% to 12%) and goiter (2% to 8%) have been reported in adult patients with acromegaly. In patients receiving octreotide for other uses, hypothyroidism has been rarely reported. Galactorrhea, adrenal suppression, gynecomastia, menstrual irregularity (e.g., amenorrhea, polymenorrhea, oligomenorrhea), vaginitis, diabetes insipidus, and pituitary apoplexy have also been reported in adult patients; however, causality to the drug has not been established. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T4) are recommended during chronic therapy.

Octreotide inhibits the pituitary secretion of growth hormone. While this effect is of benefit in adult patients with acromegaly, there is concern that growth inhibition may adversely affect children on chronic octreotide therapy for other indications (e.g., congenital hyperinsulinemia). Reports of the effect of octreotide on linear growth are conflicting. In addition, although the literature reports low serum growth hormone and/or insulin-like growth factor (IGF-1) concentrations along with growth inhibition in some patients, low concentrations do not always seem to indicate delayed growth. There is limited evidence that growth hormone suppression is dose-dependent, and catch-up growth occurs after octreotide discontinuation. In a study of 15 neonates and infants with hyperinsulinism treated with long-term octreotide (duration: 4 months to 5.9 years), 2 patients with a dosage more than 17 mcg/kg/day experienced growth deceleration. Growth hormone and IGF-1 measurements decreased from age 2 to 4 years in 1 patient with significant growth deceleration; the patient's octreotide was gradually decreased to 8 mcg/kg/day. This dosage decrease resulted in growth rate recovery and an increase in serum IGF-1 concentrations at age 6 years, indicating that suppression of growth hormone secretion and growth may be dose-dependent. Growth inhibition was negligible in the other patients in the study treated with lower octreotide dosages. Pediatric patients receiving long term octreotide therapy should be monitored for long-term growth.

Anaphylactoid reactions, including anaphylactic shock, angioedema, facial flushing, erythema, periorbital/perioral swelling (facial edema), dyspnea, cough, and abdominal pain, have been reported in patients receiving octreotide. A single case report describes successful octreotide desensitization in a child requiring octreotide therapy. Other allergic reactions reported during adult clinical trials include pruritus, urticaria, flushing, alopecia, and rash.

Octreotide may cause antibody formation. Studies in adult patients have shown up to 25% of patients treated with octreotide may develop antibodies. These antibodies do not influence octreotide efficacy, but may result in a prolonged duration of action.

Joint pain (arthralgia), backache (back pain), musculoskeletal pain, myalgia, arthritis, arthropathy, joint effusion, Raynaud's phenomenon, and generalized pain have been infrequently reported in adult patients receiving octreotide.

Headache, dizziness, fatigue, or feelings of drowsiness, weakness, and depression have been reported in adult clinical trials of octreotide. In addition, anxiety, syncope, tremor, seizures, vertigo, Bell's Palsy (cranial nerve palsies), paranoia, amnesia, neuritis have been reported in less than 1% of adult patients. Cerebral vascular disorder, aneurysm, intracranial bleeding, hemiparesis, paresis, aphasia, suicide attempt (suicidal ideation), and migraine have been reported; however, incidences are unknown and causality to the drug has not been established.

Anemia, iron deficiency, and epistaxis have been reported during clinical trials of octreotide in adults. Postmarketing reports have included thrombocytopenia, pancytopenia, petechiae, arterial thrombosis (arm), and retinal vein thrombosis (retinal thrombosis).

Respiratory and infectious adverse reactions, including cold symptoms, influenza-like symptoms, sinusitis, upper respiratory tract infection, and urinary tract infection have been reported during adult clinical trials. Pneumonia, pulmonary nodule, status asthmaticus, cellulitis, otitis, pulmonary embolism, pleural effusion, and aggravated pneumothorax have also been reported in adult patients; however, causality has not been established.

Visual impairment, blurred vision, increased intraocular pressure, and hearing loss have been reported in adult patients receiving octreotide during clinical trials. Visual field defects, scotomata, glaucoma (ocular hypertension), and deafness have been reported during postmarketing use.

Edema, pollakiuria (excessive frequent urination with increased urinary frequency), nephrolithiasis, and hematuria have been reported during clinical trials of octreotide in adult patients. Renal failure (unspecified), renal insufficiency, increased creatinine, increased creatinine kinase, malignant hyperpyrexia, breast carcinoma, and basal cell carcinoma have been reported with postmarketing use.

Octreotide is contraindicated in patients known to have an octreotide hypersensitivity or hypersensitivity to any other constituent of the formulation.

Use octreotide with caution in patients with biliary tract disease or gallbladder disease. Octreotide decreases bile secretion, modifies bile composition, and decreases gallbladder motility. Patients may be at risk for developing acute cholecystitis, ascending cholangitis, biliary obstruction, and cholestatic hepatitis during or shortly after octreotide therapy. The incidence of gallstones (cholelithiasis) does not appear to be related to age, sex, or dose but may be influenced by duration of octreotide therapy; a longer duration of octreotide use may increase the risk of cholelithiasis. In adult clinical trials of patients with acromegaly and psoriasis, less than 2% of patients treated with octreotide for 1 month or less developed gallstones; however, those on therapy 12 months or more had a 52% incidence rate of developing gallstones or biliary sludge. Gallstones are typically small and asymptomatic; in general, periodic ultrasounds are not recommended.

Although octreotide has been studied in the adjunctive treatment of acute pancreatitis, results of these studies have been controversial. Octreotide is known to increase the frequency of sphincter of Oddi contractions which could impair the flow of bile and pancreatic juices into the duodenum, possibly leading to pancreatic complications. Several cases of new onset pancreatitis have been reported in adult patients receiving octreotide therapy.

Use octreotide with caution in patients with hepatic disease. Adult patients with cirrhosis and fatty liver disease have a prolonged half-life and decreased clearance when compared to healthy subjects. Dosage adjustments may be necessary.

Use octreotide with caution in patients with severe renal failure requiring dialysis. Drug clearance is reduced by approximately 50% in this population. Dosage adjustments may be necessary.

Use octreotide with caution in patients with pre-existing diabetes mellitus. Octreotide may cause hypoglycemia or hyperglycemia by altering the balance of insulin, glucagon, and growth hormone in the body. Though glycemic effects are usually mild, overt diabetes mellitus and the need to alter dosages of insulin or other hypoglycemic agents may occur. Insulin requirements may be reduced in patients with type 1 diabetes mellitus. Conversely, insulin levels may decrease and hyperglycemia may occur in non-diabetics and in patients with type 2 diabetes with partially intact insulin reserves. Monitor blood glucose, glucose tolerance, and antidiabetic treatment periodically. In addition, octreotide may worsen symptoms of gastroparesis by reducing gut motility. Use with caution in patients with diabetic gastroparesis.

Octreotide suppresses the secretion of thyroid stimulating hormone which may result in hypothyroidism or goiter. Baseline and periodic assessment of thyroid function (TSH, total, and/or free T4) is recommended during chronic therapy. Hypothyroidism may increase the risk of prolonging the QT interval when using octreotide.

Vitamin B12 deficiency may occur in patients receiving octreotide; chronic use has been associated with an abnormal Schilling test. In addition, octreotide may cause dietary fat malabsorption. Monitor vitamin B12 levels during chronic therapy; proper nutrition and adequate weight gain should be assessed in all pediatric patients experiencing steatorrhea.

Use octreotide with caution in patients with cardiac disease and heart failure. Octreotide has been associated with sinus bradycardia, cardiac arrhythmias, QT prolongation, worsening of heart failure, and conduction abnormalities in adult acromegalic and/or carcinoid syndrome patients. Patients receiving octreotide intravenously, particularly at higher than recommended doses and/or via continuous infusion may be at risk for AV block. Consider cardiac monitoring in patients receiving intravenous octreotide. Cardiovascular medications may require dosage adjustment during octreotide therapy; use with caution in patients receiving drugs that cause QT prolongation or other ECG abnormalities. Avoid use in patients with known or suspected congenital long QT syndrome. Use octreotide with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalance. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Neonates and infants receiving octreotide may be at increased risk for developing necrotizing enterocolitis (NEC). Octreotide increases splanchnic blood vascular resistance and reduces gut blood flow. Though the pathophysiology of NEC is multifactorial and not completely understood, there have been several care reports of NEC in term neonates associated with octreotide use. Infants receiving octreotide should be closely monitored for NEC, particularly if they have other risk factors (e.g., premature neonates, congenital heart disease).

Pediatric patients receiving long term octreotide therapy should be monitored for growth inhibition. Octreotide inhibits pituitary secretion of growth hormone. While this effect is of benefit in adult patients with acromegaly, there is concern that growth inhibition may adversely effect children on chronic octreotide therapy for other indications (e.g., congenital hyperinsulinemia). Reports of the effect of octreotide on linear growth are conflicting. In addition, although the literature reports low serum growth hormone and/or insulin-like growth factor (IGF-1) concentrations along with growth inhibition in some patients, low levels do not always seem to indicate delayed growth. There is limited evidence that growth hormone suppression is dose-dependent and catch-up growth occurs after octreotide discontinuation.

Description: Octreotide is a synthetic analog of the naturally occurring hormone somatostatin. Though pharmacologic action is similar, octreotide has a longer half-life, greater selectivity for inhibiting glucagon, growth hormone, and insulin release, and a lower incidence of rebound hypersecretion after discontinuation. Octreotide affects a variety of pituitary and gastrointestinal (GI) hormones and is used for a variety of pediatric conditions including diarrhea, chylothorax, GI bleeding, and hypoglycemia due to hyperinsulinemia and sulfonylurea overdose. The drug may also be useful in children with hypothalamic obesity from a cranial insult due to a tumor, surgery, or after cranial irradiation. Octreotide's wide therapeutic actions can also lead to a variety of adverse effects. Octreotide inhibits growth hormone and is used therapeutically for acromegaly and other excessive growth conditions; though data is conflicting, there is concern that growth inhibition may adversely affect children on chronic therapy for other indications. Abdominal side effects (e.g., diarrhea, steatorrhea, abdominal pain) are common and cholelithiasis is a concern with long-term use. In addition, several case reports have associated necrotizing enterocolitis (NEC) with octreotide use in term neonates. Octreotide is not FDA-approved in pediatrics, however, the drug has been used clinically in patients as young as neonates.

For the management of diarrhea*:
Intermittent Intravenous or Subcutaneous dosage:
Neonates, Infants, Children, and Adolescents: 2-10 mcg/kg/day IV or subcutaneously given in divided doses twice daily is the most commonly reported dosage range; begin at the lower end of the dosage range and titrate to clinical response. Doses up to 18 mcg/kg/day have been reported in patients with intractable diarrhea.
Continuous Intravenous Infusion dosage:
Neonates, Infants, Children, and Adolescents: 1 mcg/kg/hour IV as a continuous infusion has been reported as efficacious in a pediatric case report of diarrhea secondary to graft vs. host disease.

For the treatment of chylothorax*:
Continuous Intravenous Infusion dosage:
Neonates: 1 to 4 mcg/kg/hour continuous IV infusion; gradually titrate (i.e., 1 mcg/kg/hour increase every 24 hours as needed) to response. Max: 10 mcg/kg/hour. Doses have ranged from 0.3 to 10 mcg/kg/hour. Duration of therapy is determined by reduction in pleural drainage; median duration of therapy is 1 week (range: 3 to 34 days). Gradually decrease infusion (i.e., 1 mcg/kg/hour every 24 hours) when chylothorax resolves. Monitor for reaccumulation.
Infants and Children: 1 to 4 mcg/kg/hour continuous IV infusion; gradually titrate (i.e., 1 mcg/kg/hour increase every 24 hours as needed) to response. Max: 10 mcg/kg/hour. Doses have ranged from 0.3 to 10 mcg/kg/hour. Duration of therapy is determined by reduction in pleural drainage; median duration of therapy is 1 week (range: 3 to 34 days). Gradually decrease infusion (i.e., 1 mcg/kg/hour every 24 hours) when chylothorax resolves. Monitor for reaccumulation.
Intermittent Subcutaneous dosage:
Neonates: 40 mcg/kg/day subcutaneously given in divided doses 3 times daily is the median effective dose. Case reports have described initial doses of 10 mg/kg/day titrated by 5 to 10 mg/kg/day every 3 to 4 days to an effective dose. Reported dosage range: 2 to 70 mcg/kg/da. The duration of therapy is determined by the reduction in pleural drainage; the median duration of therapy is 17 days (range: 8 to 43 days). Wean after 3 days of insignificant chyle output (less than 10 mL/day); decrease by 10 mcg/kg/day. Monitor for reaccumulation.
Infants and Children: 40 mcg/kg/day subcutaneously given in divided doses 3 times daily is the median effective dose. Case reports have described initial doses of 10 mg/kg/day titrated by 5 to 10 mg/kg/day every 3 to 4 days to an effective dose. Reported dosage range: 2 to 70 mcg/kg/da. The duration of therapy is determined by the reduction in pleural drainage; the median duration of therapy is 17 days (range: 8 to 43 days). Wean after 3 days of insignificant chyle output (less than 10 mL/day); decrease by 10 mcg/kg/day. Monitor for reaccumulation.

For the treatment of variceal bleeding* or nonvariceal upper GI bleeding*:
Intravenous dosage (solution for injection):
Infants, Children, and Adolescents: 1 to 2 mcg/kg IV over 5 minutes followed by 1 to 2 mcg/kg/hour continuous IV infusion. Titrate infusion to clinical response. After 24 hours of no active bleeding, taper infusion rate by 50% every 12 hours; discontinue infusion when the rate is 25% of the original dose. In a review of pediatric patients with acute GI bleeding, median duration of therapy for those with portal hypertension (n = 21) was 50 hours (range 19 hours to 7 days); for patients without portal hypertension (n = 12), median duration was 43 hours (range 3 hours to 36 days).

For the treatment of secondary hypoglycemia* due to congenital hyperinsulinemia* (e.g., hyperinsulinemic hypoglycemia):
Intermittent Subcutaneous or Intravenous dosage:
Neonates, Infants, and Children: 2-10 mcg/kg/day subcutaneously or IV given in divided doses every 6-8 hours. Titrate dosage to clinical response; tachyphylaxis may develop after several days. Reported range 5-40 mcg/kg/day. Max: 40 mcg/kg/day. Monitor blood glucose closely. If blood glucose concentrations are not maintained, may consider dividing daily dose into every 4 hour intervals or administering as a continuous infusion.
Continuous Subcutaneous or Intravenous Infusion dosage:
Neonates, Infants, and Children: 0.08-0.4 mcg/kg/hour (2-10 mcg/kg/day) subcutaneously or IV as a continuous infusion. Titrate to clinical effect. Max: 1.67 mcg/kg/hour (40 mcg/kg/day). Some experts recommend octreotide infusion with concurrent administration of glucagon; if administered concurrently, an octreotide dose of 0.4 mcg/kg/hour (10 mcg/kg/day) is recommended. Monitor blood glucose closely.

For the treatment of hypothalamic obesity* as a result of cranial injury:
Intermittent Subcutaneous dosage:
Children and Adolescents: 5 mcg/kg/day subcutaneously given in divided doses 3 times daily. May increase dose by 5 mcg/kg/day every 2 months as needed based on weight. Max: 15 mcg/kg/day subcutaneously in divided doses. This dosage resulted in insulin suppression, stabilization of BMI, decreased leptin, decreased caloric intake, increased spontaneous physical activity, and improved quality of life during a 6-month double-blind, placebo-controlled trial of 20 pediatric patients.

For the treatment of sulfonylurea overdose*:
Intermittent Subcutaneous or Intravenous dosage:
Infants, Children, and Adolescents: 1-1.5 mcg/kg/dose subcutaneously or IV every 6-12 hours. Dosage, interval, and duration may depend on amount of sulfonylurea ingested and the specific drug's half-life; titrate to clinical effect and monitor blood glucose closely. Continuous infusions (suggested initial rate 15 ng/kg/minute) have been necessary in severe refractory cases. In a retrospective review of 9 years of the American Association of Poison Control Centers National Poison Data System, a median of 1 octreotide dose (range: 1-4 doses) was administered to each patient; the doses were estimated to have been given at a median time of 11 hours (range: 1-33 hours) after sulfonylurea exposure. Of the 121 cases included in the final analysis (median patient age: 22 months; range: 8-60 months), glipizide was the sulfonylurea most frequently ingested (62% immediate-release, 7% extended-release).

Maximum Dosage Limits:
-Neonates
Dependent on indication for therapy, route of administration, and patient response. For chylothorax, 10 mcg/kg/hour continuous IV infusion; for congenital hyperinsulinemia, 40 mcg/kg/day subcutaneous or IV.
-Infants
Dependent on indication for therapy, route of administration, and patient response. For chylothorax, 10 mcg/kg/hour continuous IV infusion; for congenital hyperinsulinemia, 40 mcg/kg/day subcutaneous or IV.
-Children
Dependent on indication for therapy, route of administration, and patient response. For chylothorax, 10 mcg/kg/hour continuous IV infusion; for congenital hyperinsulinemia, 40 mcg/kg/day subcutaneous or IV; for hypothalamic obesity, 15 mcg/kg/day subcutaneous.
-Adolescents
Dependent on indication for therapy, route of administration, and patient response. For hypothalamic obesity, 15 mcg/kg/day subcutaneous.

Patients with Hepatic Impairment Dosing
Pediatric data not available. Specific guidelines for dosage adjustments in hepatic impairment are not available for the immediate-release injection.

Patients with Renal Impairment Dosing
Pediatric data not available. Initial dosage adjustments are not required in adult patients with mild, moderate, or severe renal impairment (non-dialysis patients).

Intermittent Hemodialysis
Specific guidelines for dosage adjustments in severe renal impairment or dialysis are not available for the immediate-release formulation.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: The pharmacologic effects of octreotide are similar to those of somatostatin, a hypothalamic peptide. Although the exact mechanism of action is not known, octreotide is believed to act at somatostatin receptors. Octreotide inhibits the secretion of both pituitary and gastrointestinal hormones including serotonin, gastrin, vasoactive intestinal peptide (VIP), insulin, glucagon, secretin, motilin, pancreatic polypeptide, growth hormone, and thyrotropin. Due to the number of hormones affected by octreotide, the actions of octreotide are diverse. Inhibiting the secretion of serotonin and other gastroenteric-pancreatic peptides results in decreased pancreatic and gastric acid secretions, decreased splanchnic blood flow, decreased intestinal motility, decreased gastric emptying, decreased biliary secretion and gallbladder contraction, and increased intestinal absorption of water and electrolytes.
Management of Diarrhea
Because octreotide affects many GI hormones, octreotide is useful in controlling many types of secretory diarrhea. Applications include treatment of diarrhea caused by ileostomies, acquired immunodeficiency syndrome, short bowel syndrome, radiation colitis, intestinal and pancreatic fistulas, Zollinger-Ellison syndrome, and VIPomas. Octreotide slows gut transit time, directly stimulates sodium and chloride absorption, and inhibits bicarbonate and chloride secretion. In addition, octreotide directly inhibits the release of agents, such as VIP, responsible for causing the secretion and fluids and electrolytes. As a result, stool volume decreases, and hypokalemia and achlorhydria improve.
Treatment of Chylothorax
Octreotide causes mild vasoconstriction of splanchnic vessels, including hepatic venous flow. This leads to a reduction in gastric, pancreatic, and intestinal secretions, as well as decreased intestinal absorption. Collectively these mechanisms reduce the flow of chyle and reduce accumulation in the pleural cavity.
Treatment of Hypoglycemia
Octreotide binds to the somatostatin receptor in the pancreatic beta cells, inhibiting the calcium channel. Calcium channel inhibition reduces calcium influx and thereby reduces insulin secretion. The effect of octreotide in hyperinsulinemic conditions makes it useful in the treatment of hyperinsulinemic hypoglycemia and sulfonylurea overdose.
Treatment of Gastrointestinal Bleeding
Octreotide can inhibit the secretion of hormones involved in vasodilation. This property makes octreotide useful in treating variceal bleeding. Octreotide increases splanchnic arteriolar resistance and decreases gastrointestinal and azygous blood flow, hepatic-vein wedge pressure, hepatic blood flow, portal vein pressure, and intravariceal pressure. Decreased blood flow to the portal vein reduces portal venous pressure in patients with cirrhosis or portal hypertension. A majority of patients with portal hypertension have a reduction in variceal bleeding when given octreotide. In addition, octreotide inhibits gastric acid secretion and reduces gastroduodenal blood flow, making it useful in gastrointestinal bleeding associated with other etiologies.
Management of Hypothalamic Obesity
Hypothalamic obesity is thought to be due to alteration of hypothalamic mechanisms governing satiety and hunger. Though the pathogenesis is unclear, there is a hypothesis that ventromedial hypothalamic damage causes disinhibition of vagal tone at the pancreatic beta-cell. This disinhibition leads to hypersecretion of insulin, which promotes obesity. By reducing pancreatic insulin secretion, octreotide decreases the rate of weight gain.
Management of Excessive Growth
Octreotide also inhibits the secretion of some anterior pituitary hormones. Octreotide has been studied in the treatment of acromegaly and thyrotropinomas. Octreotide's effects in treating acromegaly results from its inhibition of growth hormone (GH). In acromegalic patients, octreotide reduces serum levels of GH, resulting in a decrease in associated symptoms such as headache, hyperhidrosis, arthralgia, and finger circumference. In the treatment of thyrotropinomas, it has been reported that thyroid-stimulating hormone (TSH) levels are decreased in the majority of patients treated with octreotide. Because these tumors are rare, data on the use of octreotide in this condition are limited to case reports. Further investigation is needed to determine octreotide's role as an alternative for patients with thyrotropinomas that are refractory to surgery and radiation.

Pharmacokinetics: Octreotide acetate is administered orally and parenterally; the immediate-release injection solution should be given intravenously or subcutaneously; a long-acting depot suspension injection and an oral delayed-release dosage form are available for adult use. Approximately 65% of a dose is bound to lipoprotein and albumin in a concentration-dependent manner. The volume of distribution is estimated to be 13.6 L in adult patients. Octreotide undergoes extensive hepatic metabolism. Total body clearance ranges from 7 to 10 L/hour in adult patients. The apparent elimination half-life of immediate-release octreotide injection solution is 1.7 to 1.9 hours, which is significantly greater than somatostatin's half-life of 1 to 3 minutes. Approximately 32% of a dose is excreted in the urine as unchanged drug.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4
Octreotide suppresses growth hormone secretion, which may decrease the metabolic clearance of drugs metabolized by CYP3A4. A potential for drug-drug interactions exists when octreotide is coadministered with medications of a narrow therapeutic index that are metabolized by CYP3A4.


-Route-Specific Pharmacokinetics
Intravenous Route
Intravenous and subcutaneous octreotide are bioequivalent; peak concentrations and AUC are dose-proportional.

Subcutaneous Route
Octreotide is absorbed rapidly and completely after subcutaneous injection. Distribution of octreotide from plasma occurs rapidly, with an apparent distribution half-life of 12 minutes. In adult patients, peak concentrations of 5.2 ng/mL occur within 25 minutes after a 100 mcg dose. The effects of subcutaneous octreotide are variable but can last for up to 12 hours, depending on the indication for use.


-Special Populations
Pediatrics
Children and Adolescents
Limited pharmacokinetic data exist in children; no specific pharmacokinetic data are available for octreotide injection solution given IV or subcutaneously.

Hepatic Impairment
The effect of hepatic impairment on the disposition of octreotide is unknown. After administration of octreotide immediate-release injection solution subcutaneously or IV, adult patients with cirrhosis have demonstrated a prolonged octreotide half-life (3.7 hours) and decreased clearance (5.9 L/hour), while adult patients with fatty liver disease have shown a similar half-life (3.4 L/hour) to normal adults, but a larger reduction in clearance (8.2 L/hour).

Renal Impairment
Patients with renal impairment have a reduced total body clearance and prolonged elimination half-life of octreotide (injection solution, given IV or subcutaneously). In adult patients, those with mild renal impairment (CrCl 40 to 60 mL/minute) have a clearance of 8.8 L/hour and a half-life of 2.4 hours; patients with moderate impairment (10 to 39 mL/minute) have a clearance of 7.3 L/hour and a half-life of 3 hours. Adult patients with severe renal impairment (CrCl less than 10 mL/minute) have a clearance of 7.6 L/hour and a half-life of 3.1 hours. Patients with severe renal failure requiring dialysis have a clearance of 4.5 L/hour, half of that found in healthy subjects (10 L/hour).

Other
Patients with Gigantism/Acromegaly
Pharmacokinetics in adult patients with acromegaly differ from those in healthy volunteers. Protein binding is less, 41% compared to 65% in healthy volunteers. Volume of distribution is larger (21.6 +/- 8.5 L vs. 13.6 L), and total body clearance is increased (18 L/hour vs. 7 to 10 L/hour). Elimination half-life is similar in both populations. After a 100 mcg subcutaneous dose in adults with acromegaly, peak concentrations (2.8 ng/mL) are lower and occur after a prolonged period (42 minutes) when compared to healthy adult patients (Cmax 5.2 ng/mL; Tmax 25 minutes). Though the pharmacokinetic data in pediatric patients with gigantism is unknown, adult pharmacokinetic parameters may provide some guidance.