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Indications/Uses
Symptomatic control and reduction of growth hormone (GH) and IGF-1 plasma levels in patients with acromegaly who are inadequately controlled by surgery or radiotherapy.
Octreotide (Sandostatin) treatment is also indicated for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.
Relief of symptoms associated with functional gastro-entero-pancreatic (GEP) endocrine tumors: Carcinoid tumors with features of the carcinoid syndrome; VIPomas; glucagonomas; Gastrinomas/Zollinger-Ellison syndrome, usually in conjunction with proton-pump inhibitors or H2-antagonist therapy; Insulinomas, for pre-operative control of hypoglycemia and maintenance therapy; GRFomas.
Octreotide (Sandostatin) is not an antitumor therapy and is not curative in these patients.
Control of refractory diarrhea associated with AIDS.
Prevention of complications following pancreatic surgery.
Emergency management to stop bleeding and to protect from re-bleeding owing to gastroesophageal varices in patients with cirrhosis. Octreotide (Sandostatin) is to be used in association with specific treatment such as endoscopic sclerotherapy.
Octreotide (Sandostatin) treatment is also indicated for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.
Relief of symptoms associated with functional gastro-entero-pancreatic (GEP) endocrine tumors: Carcinoid tumors with features of the carcinoid syndrome; VIPomas; glucagonomas; Gastrinomas/Zollinger-Ellison syndrome, usually in conjunction with proton-pump inhibitors or H2-antagonist therapy; Insulinomas, for pre-operative control of hypoglycemia and maintenance therapy; GRFomas.
Octreotide (Sandostatin) is not an antitumor therapy and is not curative in these patients.
Control of refractory diarrhea associated with AIDS.
Prevention of complications following pancreatic surgery.
Emergency management to stop bleeding and to protect from re-bleeding owing to gastroesophageal varices in patients with cirrhosis. Octreotide (Sandostatin) is to be used in association with specific treatment such as endoscopic sclerotherapy.
Dosage/Direction for Use
General target population: Acromegaly: Initially 0.05 to 0.1 mg by s.c. injection every 8 or 12 hours. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH <2.5 ng/mL; IGF-1 within normal range) and clinical symptoms, and on tolerability. In most patients, the optimal daily dose will be 0.3 mg. A maximum dose of 1.5 mg per day should not be exceeded. For patients on a stable dose of octreotide (Sandostatin), assessment of IGF-1 and/or GH should be made every 6 months.
If no relevant reduction in IGF-1 and/or GH levels and no improvement in clinical symptoms have been achieved within 3 months of starting treatment with octreotide (Sandostatin), therapy should be discontinued.
Gastro-entero-pancreatic endocrine tumors: Initially 0.05 mg once or twice daily by s.c. injection. Depending on clinical response, effect on levels of tumor-produced hormones (in cases of carcinoid tumors, on the urinary excretion of 5-hydroxyindole acetic acid), and on tolerability, dosage can be gradually increased to 0.1 to 0.2 mg 3 times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses have to be adjusted individually.
In carcinoid tumors, if there is no beneficial response within 1 week of treatment with octreotide (Sandostatin) at the maximum tolerated dose, therapy should not be continued.
AIDS-related refractory diarrhea: The data suggest that 0.1 mg 3 times per day by s.c. injection is the optimal starting dose. If diarrhea is not controlled after 1 week of treatment, the dose should be titrated on an individual basis up to 0.25 mg 3 times per day. Dose adjustment should be based on assessment of stool output and on tolerability.
If within 1 week of treatment with octreotide (Sandostatin) at a dose of 0.25 mg 3 times per day no improvement is achieved, therapy should be discontinued.
Complications following pancreatic surgery: 0.1 mg 3 times daily by s.c. injection for 7 consecutive days, starting on the day of operation at least 1 hr before laparotomy.
Bleeding gastroesophageal varices: 25 micrograms/hour for 5 days by continuous i.v. infusion. Octreotide (Sandostatin) can be used in dilution with physiological saline.
In cirrhotic patients with bleeding gastro-esophageal varices, octreotide (Sandostatin) has been well-tolerated at continuous i.v. doses of up to 50 microgram/hour for 5 days (see OVERDOSAGE).
Special Populations: Hepatic impairment: In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage.
Renal impairment: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection, therefore no dose adjustment of octreotide (Sandostatin) is necessary.
Pediatric patients (below 18 years): Experience with octreotide (Sandostatin) in children is limited.
Geriatric patients (65 years or above): There is no evidence of reduced tolerability or altered dosage requirements in elderly patients treated with octreotide (Sandostatin).
If no relevant reduction in IGF-1 and/or GH levels and no improvement in clinical symptoms have been achieved within 3 months of starting treatment with octreotide (Sandostatin), therapy should be discontinued.
Gastro-entero-pancreatic endocrine tumors: Initially 0.05 mg once or twice daily by s.c. injection. Depending on clinical response, effect on levels of tumor-produced hormones (in cases of carcinoid tumors, on the urinary excretion of 5-hydroxyindole acetic acid), and on tolerability, dosage can be gradually increased to 0.1 to 0.2 mg 3 times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses have to be adjusted individually.
In carcinoid tumors, if there is no beneficial response within 1 week of treatment with octreotide (Sandostatin) at the maximum tolerated dose, therapy should not be continued.
AIDS-related refractory diarrhea: The data suggest that 0.1 mg 3 times per day by s.c. injection is the optimal starting dose. If diarrhea is not controlled after 1 week of treatment, the dose should be titrated on an individual basis up to 0.25 mg 3 times per day. Dose adjustment should be based on assessment of stool output and on tolerability.
If within 1 week of treatment with octreotide (Sandostatin) at a dose of 0.25 mg 3 times per day no improvement is achieved, therapy should be discontinued.
Complications following pancreatic surgery: 0.1 mg 3 times daily by s.c. injection for 7 consecutive days, starting on the day of operation at least 1 hr before laparotomy.
Bleeding gastroesophageal varices: 25 micrograms/hour for 5 days by continuous i.v. infusion. Octreotide (Sandostatin) can be used in dilution with physiological saline.
In cirrhotic patients with bleeding gastro-esophageal varices, octreotide (Sandostatin) has been well-tolerated at continuous i.v. doses of up to 50 microgram/hour for 5 days (see OVERDOSAGE).
Special Populations: Hepatic impairment: In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of the maintenance dosage.
Renal impairment: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection, therefore no dose adjustment of octreotide (Sandostatin) is necessary.
Pediatric patients (below 18 years): Experience with octreotide (Sandostatin) in children is limited.
Geriatric patients (65 years or above): There is no evidence of reduced tolerability or altered dosage requirements in elderly patients treated with octreotide (Sandostatin).
Overdosage
A limited number of accidental overdoses of octreotide (Sandostatin) in adults and children have been reported. In adults, the doses ranged from 2,400-6,000 microgram/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 microgram t.i.d.). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis. Atrioventricular blocks (including complete atrioventricular block) were reported in patients receiving higher doses of continuous infusion (100 microgram/hour) and/or bolus of octreotide (Sandostatin) intravenously (50 microgram bolus followed by 50 microgram/hour continuous infusion).
In children, the doses ranged from 50-3,000 microgram/day administered by continuous infusion (2.1-500 microgram/hour) or subcutaneously (50-100 microgram). The only adverse event reported was mild hyperglycemia.
No unexpected adverse events have been reported in cancer patients receiving octreotide (Sandostatin) at doses of 3,000-30,000 microgram/day in divided doses subcutaneously.
Treatment: The management of overdosage is symptomatic. Patients who received higher than recommended doses of intravenous octreotide are at increased risk of higher degree atrioventricular blocks and should be kept under appropriate cardiac monitoring.
In children, the doses ranged from 50-3,000 microgram/day administered by continuous infusion (2.1-500 microgram/hour) or subcutaneously (50-100 microgram). The only adverse event reported was mild hyperglycemia.
No unexpected adverse events have been reported in cancer patients receiving octreotide (Sandostatin) at doses of 3,000-30,000 microgram/day in divided doses subcutaneously.
Treatment: The management of overdosage is symptomatic. Patients who received higher than recommended doses of intravenous octreotide are at increased risk of higher degree atrioventricular blocks and should be kept under appropriate cardiac monitoring.
Contraindications
Known hypersensitivity to octreotide or to any of the excipients (see DESCRIPTION).
Special Precautions
General: As GH-secreting pituitary tumors may sometimes expand, causing serious complications (e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of tumor expansion appears, alternative procedures may be advisable.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see USE IN PREGNANCY & LACTATION).
Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.
Cardiovascular related events: Cases of bradycardia have been reported (frequency: common). Dose adjustments of drugs such as, beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.
Gallbladder and related events: Cholelithiasis is a very common event during octreotide (Sandostatin) treatment and may be associated with cholecystitis and biliary duct dilatation (see ADVERSE DRUG REACTIONS). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients taking octreotide (Sandostatin) in the post-marketing setting. Ultrasonic examination of the gallbladder before, and at about 6- to 12-month intervals during octreotide (Sandostatin) therapy is therefore recommended.
GEP endocrine tumors: During the treatment of GEP endocrine tumors, there may be rare instances of sudden escape from symptomatic control by octreotide (Sandostatin), with rapid recurrence of severe symptoms.
Glucose metabolism: Because of its inhibitory action on growth hormone, glucagon, and insulin, octreotide (Sandostatin) may affect glucose regulation. Post-prandial glucose tolerance may be impaired and, in some instances, the state of persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia has also been reported.
In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycemia. These patients should be closely monitored during initiation of octreotide (Sandostatin) therapy and at each change of dosage. Marked fluctuations in blood glucose concentration may possibly be reduced by smaller, more frequently administered doses.
Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by administration of octreotide (Sandostatin). In non-diabetics and type II diabetics with partially intact insulin reserves, octreotide (Sandostatin) administration can result in prandial increases in glycemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Esophageal varices: Since, following bleeding episodes from esophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.
Local site reactions: In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the s.c. injection site only at the highest dose (about 40 times the maximum human dose). No hyperplastic or neoplastic lesions occurred at the s.c. injection site in a 52-week dog toxicity study. There have been no reports of tumor formation at the injection sites in patients treated with octreotide (Sandostatin) for up to 15 years. All the information available at present indicates that the findings in rats are species specific and have no significance for the use of the drug in humans.
Nutrition: Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended during therapy with octreotide (Sandostatin) in patients who have a history of vitamin B12 deprivation.
The therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see USE IN PREGNANCY & LACTATION).
Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.
Cardiovascular related events: Cases of bradycardia have been reported (frequency: common). Dose adjustments of drugs such as, beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.
Gallbladder and related events: Cholelithiasis is a very common event during octreotide (Sandostatin) treatment and may be associated with cholecystitis and biliary duct dilatation (see ADVERSE DRUG REACTIONS). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients taking octreotide (Sandostatin) in the post-marketing setting. Ultrasonic examination of the gallbladder before, and at about 6- to 12-month intervals during octreotide (Sandostatin) therapy is therefore recommended.
GEP endocrine tumors: During the treatment of GEP endocrine tumors, there may be rare instances of sudden escape from symptomatic control by octreotide (Sandostatin), with rapid recurrence of severe symptoms.
Glucose metabolism: Because of its inhibitory action on growth hormone, glucagon, and insulin, octreotide (Sandostatin) may affect glucose regulation. Post-prandial glucose tolerance may be impaired and, in some instances, the state of persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia has also been reported.
In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory action on insulin, may increase the depth and prolong the duration of hypoglycemia. These patients should be closely monitored during initiation of octreotide (Sandostatin) therapy and at each change of dosage. Marked fluctuations in blood glucose concentration may possibly be reduced by smaller, more frequently administered doses.
Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by administration of octreotide (Sandostatin). In non-diabetics and type II diabetics with partially intact insulin reserves, octreotide (Sandostatin) administration can result in prandial increases in glycemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.
Esophageal varices: Since, following bleeding episodes from esophageal varices, there is an increased risk for the development of insulin-dependent diabetes or for changes in insulin requirement in patients with pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.
Local site reactions: In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the s.c. injection site only at the highest dose (about 40 times the maximum human dose). No hyperplastic or neoplastic lesions occurred at the s.c. injection site in a 52-week dog toxicity study. There have been no reports of tumor formation at the injection sites in patients treated with octreotide (Sandostatin) for up to 15 years. All the information available at present indicates that the findings in rats are species specific and have no significance for the use of the drug in humans.
Nutrition: Octreotide may alter absorption of dietary fats in some patients.
Depressed vitamin B12 levels and abnormal Schilling's tests have been observed in some patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended during therapy with octreotide (Sandostatin) in patients who have a history of vitamin B12 deprivation.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women. In the post-marketing experience data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases, the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 microgram/day of octreotide (Sandostatin) s.c. or 20-30 mg/month of octreotide (Sandostatin) LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies. In most of the cases with known outcome, normal newborns were reported but also several spontaneous abortions during the first trimester, and a few induced abortions.
There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.
Studies in laboratory animals have not shown reproductive toxicological effects. A transient growth retardation of offspring was observed in rats, possibly consequent upon the specific endocrine profile of the species tested (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Octreotide (Sandostatin) should only be prescribed to pregnant woman under compelling circumstances (see PRECAUTIONS).
Breast-feeding: It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during octreotide (Sandostatin) treatment.
Fertility: It is not known whether octreotide has an effect on human fertility. Octreotide did not impair fertility in male and female rats at doses of up to 1 mg/kg body weight per day (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.
Studies in laboratory animals have not shown reproductive toxicological effects. A transient growth retardation of offspring was observed in rats, possibly consequent upon the specific endocrine profile of the species tested (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Octreotide (Sandostatin) should only be prescribed to pregnant woman under compelling circumstances (see PRECAUTIONS).
Breast-feeding: It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk. Patients should not breast-feed during octreotide (Sandostatin) treatment.
Fertility: It is not known whether octreotide has an effect on human fertility. Octreotide did not impair fertility in male and female rats at doses of up to 1 mg/kg body weight per day (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).
Adverse Reactions
Summary of the Safety Profile: The most frequent adverse reactions reported during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.
The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction (e.g., decreased thyroid-stimulating hormone [TSH], decreased Total T4, and decreased Free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia.
Tabulated summary of adverse drug reactions from clinical trials: The following adverse drug reactions (ADRs), listed in Table 1, have been accumulated from clinical studies with octreotide: Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 1.)
The most commonly reported adverse reactions in clinical trials with octreotide administration were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sludge, thyroid dysfunction (e.g., decreased thyroid-stimulating hormone [TSH], decreased Total T4, and decreased Free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia.
Tabulated summary of adverse drug reactions from clinical trials: The following adverse drug reactions (ADRs), listed in Table 1, have been accumulated from clinical studies with octreotide: Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent first, using the following convention: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 1.)
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with octreotide via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. ADRs are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 2.)
Description of selected adverse drug reactions: Gastrointestinal disorders and nutrition: In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.
Although measured fecal fat excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption.
Occurrence of gastrointestinal side effects may be reduced by avoiding meals around the time of octreotide (Sandostatin) s.c. administration, that is, by injecting between meals or on retiring to bed.
Gallbladder and related reactions: Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile secretion, which may lead to gallbladder abnormalities or sludge. The incidence of gallstone formation with octreotide (Sandostatin) treatment is estimated to be between 15 to 30%. The incidence in the general population is 5 to 20%. The presence of gallstones or biliary sludge in octreotide (Sandostatin)-treated patients is largely asymptomatic. Symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery. (See Recommendation for the management of patients during octreotide (Sandostatin) treatment with respect to the development of gallstones under Patient Counselling Information).
Injection site reactions: Pain or a sensation of stinging, tingling or burning at the site of s.c. injection can occur, with redness and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection, or by injecting a smaller volume using a more concentrated solution.
Cardiac disorders: Bradycardia is a common adverse reaction with somatostatin analogues. In both acromegalic and carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave changes. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac diseases (see PRECAUTIONS).
Pancreatitis: Cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide (Sandostatin) s.c. treatment. In very rare instances, acute pancreatitis has been reported within the first hours or days of octreotide (Sandostatin) s.c. treatment and resolved on withdrawal of the drug.
Hypersensitivity and anaphylactic reactions: Hypersensitivity and allergic reactions have been reported during post-marketing experience. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.
Thrombocytopenia: Thrombocytopenia has been reported during post-marketing experience, particularly during treatment with octreotide (Sandostatin) (i.v.) in patients with cirrhosis of the liver. This is reversible after discontinuation of treatment.
Drug Interactions
Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may be necessary when octreotide (Sandostatin) is administered concomitantly (see PRECAUTIONS).
Dose adjustments of insulin and antidiabetic medicinal products may be required when octreotide (Sandostatin) is administered concomitantly (see PRECAUTIONS).
Octreotide (Sandostatin) has been found to reduce the intestinal absorption of ciclosporin and to delay that of cimetidine.
Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.
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 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 should therefore be used with caution (e.g. quinidine, terfenadine).
Dose adjustments of insulin and antidiabetic medicinal products may be required when octreotide (Sandostatin) is administered concomitantly (see PRECAUTIONS).
Octreotide (Sandostatin) has been found to reduce the intestinal absorption of ciclosporin and to delay that of cimetidine.
Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.
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 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 should therefore be used with caution (e.g. quinidine, terfenadine).
Caution For Usage
Instructions for Use and Handling: Subcutaneous Administration: Patients who are to self-administer the drug by s.c. injection must receive precise directions from the physician or the nurse.
To reduce local discomfort, it is recommended that the solution should be at room temperature before injection. Multiple injections at short intervals at the same site should be avoided.
Ampoules should be opened just prior to administration and any unused portion discarded.
Intravenous infusion: Parenteral drug products should be inspected visually for discoloration and particulate matter prior to administration.
Octreotide (Sandostatin) is physically and chemically stable for 24 hours in sterile physiological saline solutions or sterile solutions of dextrose (glucose) 5% in water. However, because octreotide (Sandostatin) can affect glucose homeostasis, it is recommended that physiological saline solutions be used rather than dextrose. The diluted solutions are physically and chemically stable for at least 24 hours below 25°C. From a microbiological point of view, the diluted solution should preferably be used immediately. If the solution is not used immediately, storage prior to use is the responsibility of the user and should be at 2 to 8°C. Before administration, the solution has to be brought to room temperature again.
The cumulated time between reconstitution, dilution with infusion media, storage in a refrigerator, and end of administration must not be longer than 24 hours.
In cases where octreotide (Sandostatin) is to be administered by i.v. infusion, the contents of one 0.5 mg ampoule should normally be dissolved in 60 mL physiological saline, and the resulting solution should be infused by means of an infusion pump. This should be repeated as often as necessary until the prescribed duration of treatment is reached. Octreotide (Sandostatin) has also been infused in lower concentrations.
Special Precautions for Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
To reduce local discomfort, it is recommended that the solution should be at room temperature before injection. Multiple injections at short intervals at the same site should be avoided.
Ampoules should be opened just prior to administration and any unused portion discarded.
Intravenous infusion: Parenteral drug products should be inspected visually for discoloration and particulate matter prior to administration.
Octreotide (Sandostatin) is physically and chemically stable for 24 hours in sterile physiological saline solutions or sterile solutions of dextrose (glucose) 5% in water. However, because octreotide (Sandostatin) can affect glucose homeostasis, it is recommended that physiological saline solutions be used rather than dextrose. The diluted solutions are physically and chemically stable for at least 24 hours below 25°C. From a microbiological point of view, the diluted solution should preferably be used immediately. If the solution is not used immediately, storage prior to use is the responsibility of the user and should be at 2 to 8°C. Before administration, the solution has to be brought to room temperature again.
The cumulated time between reconstitution, dilution with infusion media, storage in a refrigerator, and end of administration must not be longer than 24 hours.
In cases where octreotide (Sandostatin) is to be administered by i.v. infusion, the contents of one 0.5 mg ampoule should normally be dissolved in 60 mL physiological saline, and the resulting solution should be infused by means of an infusion pump. This should be repeated as often as necessary until the prescribed duration of treatment is reached. Octreotide (Sandostatin) has also been infused in lower concentrations.
Special Precautions for Disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Store at 2°C - 8°C (in a refrigerator).
Do not freeze.
Keep container in the outer carton in order to protect from light.
For prolonged storage, octreotide (Sandostatin) ampules must be stored at 2 to 8°C.
For day-to-day use, they may be stored not above 30°C for up to 2 weeks.
Do not freeze.
Keep container in the outer carton in order to protect from light.
For prolonged storage, octreotide (Sandostatin) ampules must be stored at 2 to 8°C.
For day-to-day use, they may be stored not above 30°C for up to 2 weeks.
Action
Pharmacology: Mechanism of Action: Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the GEP endocrine system.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.
In healthy subjects octreotide (Sandostatin) has been shown to inhibit: release of GH stimulated by arginine, exercise- and insulin-induced hypoglycemia, postprandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon, thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).
Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).
In acromegalic patients octreotide (Sandostatin) lowers plasma levels of GH and IGF-1. A GH reduction by 50% or more occurs in up to 90% patients, and a reduction of serum GH to < 5 ng/mL can be achieved in about half of the cases. In most patients octreotide (Sandostatin) markedly reduces the clinical symptoms of the disease, such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paresthesia. In patients with a large pituitary adenoma, octreotide (Sandostatin) treatment may result in some shrinkage of the tumor mass.
In patients with functional tumors of the GEP endocrine system, octreotide (Sandostatin), because of its diverse endocrine effects, modifies a number of clinical features. Clinical improvement and symptomatic benefit occur in patients who still have symptoms related to their tumors despite previous therapies, which may include surgery, hepatic artery embolization, and various chemotherapies, e.g. streptozotocin and 5-fluorouracil.
Pharmacodynamics: Octreotide's effects in the different tumor types are as follows.
Carcinoid tumors: Administration of octreotide (Sandostatin) may result in improvement of symptoms, particularly of flush and diarrhea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.
VIPomas: The biochemical characteristic of these tumors is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide (Sandostatin) results in alleviation of the severe secretory diarrhea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computer tomography scanning suggests a slowing or arrest of progression of the tumor, or even tumor shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.
Glucagonomas: Administration of octreotide (Sandostatin) results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide (Sandostatin) on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycemic agents. Octreotide (Sandostatin) produces improvement of diarrhea, and hence weight gain, in those patients affected. Although administration of octreotide (Sandostatin) often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
Gastrinomas/Zollinger-Ellison syndrome: Although therapy with proton pump inhibitors or H2-receptor blocking agents controls the recurrent peptic ulceration which results from chronic gastrin-stimulated hypersecretion of gastric acid, such control may be incomplete. Diarrhea may also be a prominent symptom not alleviated by this therapy. Octreotide (Sandostatin) alone or in conjunction with proton pump inhibitors or H2-receptor antagonists may reduce gastric acid hypersecretion and improve symptoms, including diarrhea. Other symptoms possibly due to peptide production by the tumor, e.g. flush, may also be relieved. Plasma gastrin levels fall in some patients.
Insulinomas: Administration of octreotide (Sandostatin) produces a fall in circulating immunoreactive insulin, which may, however, be of short duration (about 2 hours). In patients with operable tumors octreotide (Sandostatin) may help to restore and maintain normoglycemia pre-operatively. In patients with inoperable benign or malignant tumors, glycemic control may be improved without concomitant sustained reduction in circulating insulin levels.
These rare tumors are characterized by production of GH releasing factor (GRF) alone or in conjunction with other active peptides. Octreotide (Sandostatin) produces improvement in the features and symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH secretion, and a reduction in pituitary enlargement may follow.
In patients with acquired immune deficiency syndrome (AIDS)-related refractory diarrhea, octreotide (Sandostatin) produces partial or complete control of stool output in about one-third of patients with diarrhea unresponsive to conventional anti-infective and/or antidiarrheal agents.
For patients undergoing pancreatic surgery, the peri- and post-operative administration of octreotide (Sandostatin) reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).
In patients presenting with bleeding gastro-esophageal varices due to underlying cirrhosis, octreotide (Sandostatin) administration in combination with specific treatment (e.g. sclerotherapy) is associated with better control of bleeding and early re-bleeding, reduced transfusion requirements, and improved 5-day survival. While the precise mode of action of octreotide (Sandostatin) is not fully elucidated, it is postulated that octreotide (Sandostatin) reduces splanchnic blood flow through inhibition of vaso-active hormones (e.g. VIP, glucagon).
Clinical Studies: Not applicable. Octreotide (Sandostatin) is an established product.
Pharmacokinetics: Absorption: After s.c. injection, octreotide (Sandostatin) is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.
Distribution: The volume of distribution is 0.27 L/kg, and the total body clearance 160 mL/min. Plasma protein binding amounts to 65%. The amount of octreotide (Sandostatin) bound to blood cells is negligible.
Elimination: The elimination half-life after s.c. administration is 100 minutes. After i.v. injection, the elimination is biphasic, with half-lives of 10 and 90 minutes. Most of the peptide is eliminated via the feces, while approximately 32% is excreted unchanged into the urine.
Special patient population: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection. The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.
Toxicology: Non-Clinical Safety Data: Repeat-dose toxicity An initial 26-week i.v. toxicity study in dogs carried out at dose levels of up to 0.5 mg/kg once daily revealed proliferative/degenerative changes in acidophil prolactin-containing cells in the pituitary. Further investigations showed this to be within the physiological range of the species used. Female Rhesus monkeys receiving 0.5 mg/kg twice daily (b.i.d) for 3 weeks failed to reveal pituitary changes, and there were no alterations of basal levels of plasma growth hormone, prolactin, or glucose.
Whereas the acidic vehicle produced inflammation and fibroplasia upon repeated s.c. injection in rats, there was no evidence that octreotide acetate causes delayed-type hypersensitivity reactions when injected intradermally in guinea pigs in 0.1% solution in 0.9% sterile saline.
Genotoxicity: Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro in validated bacterial and mammalian cell test systems. In one study, an increased frequency of chromosomal changes were observed in V79 Chinese hamster cells, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate. In vivo, no clastogenic activity was observed in the bone marrow of mice treated with octreotide i.v. (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay on sperm heads.
Carcinogenicity/chronic toxicity: In rats receiving octreotide acetate at daily doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumors occurred also in the control rats, however development of these tumors was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were observed neither in mice receiving daily s.c. injections of octreotide at doses up to 2 mg/kg for up to 99 weeks, nor in dogs which were treated with daily s.c. doses of the drug for 52 weeks.
The 116-week carcinogenicity study in rats with s.c. octreotide also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest s.c. dose level of 1.25 mg/kg per day. The finding was associated with an increased incidence of endometritis, a decreased number of ovarian corpora lutea, a reduction in mammary adenomas and the presence of uterine glandular and luminal dilation, suggesting a state of hormonal imbalance. The available information clearly indicates that the findings of endocrine-mediated tumors in rats are species-specific and are not relevant for the use of the drug in humans.
Reproduction: Reproduction studies have been performed in rats and rabbits at parenteral doses of up to 1 mg/kg body weight per day. Some retardation of the physiological growth was noted in the offspring of rats which was transient and most likely attributable to GH inhibition brought about by excessive pharmacodynamic activity. There was no evidence of teratogenic, embryo/fetal or other reproduction effects due to octreotide.
In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than somatostatin is, with greater selectivity for GH and glucagon suppression.
In healthy subjects octreotide (Sandostatin) has been shown to inhibit: release of GH stimulated by arginine, exercise- and insulin-induced hypoglycemia, postprandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine system, and arginine-stimulated release of insulin and glucagon, thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).
Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients with acromegaly).
In acromegalic patients octreotide (Sandostatin) lowers plasma levels of GH and IGF-1. A GH reduction by 50% or more occurs in up to 90% patients, and a reduction of serum GH to < 5 ng/mL can be achieved in about half of the cases. In most patients octreotide (Sandostatin) markedly reduces the clinical symptoms of the disease, such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paresthesia. In patients with a large pituitary adenoma, octreotide (Sandostatin) treatment may result in some shrinkage of the tumor mass.
In patients with functional tumors of the GEP endocrine system, octreotide (Sandostatin), because of its diverse endocrine effects, modifies a number of clinical features. Clinical improvement and symptomatic benefit occur in patients who still have symptoms related to their tumors despite previous therapies, which may include surgery, hepatic artery embolization, and various chemotherapies, e.g. streptozotocin and 5-fluorouracil.
Pharmacodynamics: Octreotide's effects in the different tumor types are as follows.
Carcinoid tumors: Administration of octreotide (Sandostatin) may result in improvement of symptoms, particularly of flush and diarrhea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid.
VIPomas: The biochemical characteristic of these tumors is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of octreotide (Sandostatin) results in alleviation of the severe secretory diarrhea typical of the condition, with consequent improvement in quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, e.g. hypokalemia, enabling enteral and parenteral fluid and electrolyte supplementation to be withdrawn. In some patients, computer tomography scanning suggests a slowing or arrest of progression of the tumor, or even tumor shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.
Glucagonomas: Administration of octreotide (Sandostatin) results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide (Sandostatin) on the state of mild diabetes mellitus which frequently occurs is not marked and, in general, does not result in a reduction of requirements for insulin or oral hypoglycemic agents. Octreotide (Sandostatin) produces improvement of diarrhea, and hence weight gain, in those patients affected. Although administration of octreotide (Sandostatin) often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
Gastrinomas/Zollinger-Ellison syndrome: Although therapy with proton pump inhibitors or H2-receptor blocking agents controls the recurrent peptic ulceration which results from chronic gastrin-stimulated hypersecretion of gastric acid, such control may be incomplete. Diarrhea may also be a prominent symptom not alleviated by this therapy. Octreotide (Sandostatin) alone or in conjunction with proton pump inhibitors or H2-receptor antagonists may reduce gastric acid hypersecretion and improve symptoms, including diarrhea. Other symptoms possibly due to peptide production by the tumor, e.g. flush, may also be relieved. Plasma gastrin levels fall in some patients.
Insulinomas: Administration of octreotide (Sandostatin) produces a fall in circulating immunoreactive insulin, which may, however, be of short duration (about 2 hours). In patients with operable tumors octreotide (Sandostatin) may help to restore and maintain normoglycemia pre-operatively. In patients with inoperable benign or malignant tumors, glycemic control may be improved without concomitant sustained reduction in circulating insulin levels.
These rare tumors are characterized by production of GH releasing factor (GRF) alone or in conjunction with other active peptides. Octreotide (Sandostatin) produces improvement in the features and symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH secretion, and a reduction in pituitary enlargement may follow.
In patients with acquired immune deficiency syndrome (AIDS)-related refractory diarrhea, octreotide (Sandostatin) produces partial or complete control of stool output in about one-third of patients with diarrhea unresponsive to conventional anti-infective and/or antidiarrheal agents.
For patients undergoing pancreatic surgery, the peri- and post-operative administration of octreotide (Sandostatin) reduces the incidence of typical postoperative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).
In patients presenting with bleeding gastro-esophageal varices due to underlying cirrhosis, octreotide (Sandostatin) administration in combination with specific treatment (e.g. sclerotherapy) is associated with better control of bleeding and early re-bleeding, reduced transfusion requirements, and improved 5-day survival. While the precise mode of action of octreotide (Sandostatin) is not fully elucidated, it is postulated that octreotide (Sandostatin) reduces splanchnic blood flow through inhibition of vaso-active hormones (e.g. VIP, glucagon).
Clinical Studies: Not applicable. Octreotide (Sandostatin) is an established product.
Pharmacokinetics: Absorption: After s.c. injection, octreotide (Sandostatin) is rapidly and completely absorbed. Peak plasma concentrations are reached within 30 minutes.
Distribution: The volume of distribution is 0.27 L/kg, and the total body clearance 160 mL/min. Plasma protein binding amounts to 65%. The amount of octreotide (Sandostatin) bound to blood cells is negligible.
Elimination: The elimination half-life after s.c. administration is 100 minutes. After i.v. injection, the elimination is biphasic, with half-lives of 10 and 90 minutes. Most of the peptide is eliminated via the feces, while approximately 32% is excreted unchanged into the urine.
Special patient population: Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c. injection. The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease.
Toxicology: Non-Clinical Safety Data: Repeat-dose toxicity An initial 26-week i.v. toxicity study in dogs carried out at dose levels of up to 0.5 mg/kg once daily revealed proliferative/degenerative changes in acidophil prolactin-containing cells in the pituitary. Further investigations showed this to be within the physiological range of the species used. Female Rhesus monkeys receiving 0.5 mg/kg twice daily (b.i.d) for 3 weeks failed to reveal pituitary changes, and there were no alterations of basal levels of plasma growth hormone, prolactin, or glucose.
Whereas the acidic vehicle produced inflammation and fibroplasia upon repeated s.c. injection in rats, there was no evidence that octreotide acetate causes delayed-type hypersensitivity reactions when injected intradermally in guinea pigs in 0.1% solution in 0.9% sterile saline.
Genotoxicity: Octreotide and/or its metabolites were devoid of mutagenic potential when investigated in vitro in validated bacterial and mammalian cell test systems. In one study, an increased frequency of chromosomal changes were observed in V79 Chinese hamster cells, albeit at high and cytotoxic concentrations only. Chromosomal aberrations were however not increased in human lymphocytes incubated with octreotide acetate. In vivo, no clastogenic activity was observed in the bone marrow of mice treated with octreotide i.v. (micronucleus test) and no evidence of genotoxicity was obtained in male mice using a DNA repair assay on sperm heads.
Carcinogenicity/chronic toxicity: In rats receiving octreotide acetate at daily doses up to 1.25 mg/kg body weight, fibrosarcomas were observed, predominantly in a number of male animals, at the s.c. injection site after 52, 104 and 113/116 weeks. Local tumors occurred also in the control rats, however development of these tumors was attributed to disordered fibroplasia produced by sustained irritant effects at the injection sites, enhanced by the acidic lactic acid/mannitol vehicle. This non-specific tissue reaction appeared to be particular to rats. Neoplastic lesions were observed neither in mice receiving daily s.c. injections of octreotide at doses up to 2 mg/kg for up to 99 weeks, nor in dogs which were treated with daily s.c. doses of the drug for 52 weeks.
The 116-week carcinogenicity study in rats with s.c. octreotide also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest s.c. dose level of 1.25 mg/kg per day. The finding was associated with an increased incidence of endometritis, a decreased number of ovarian corpora lutea, a reduction in mammary adenomas and the presence of uterine glandular and luminal dilation, suggesting a state of hormonal imbalance. The available information clearly indicates that the findings of endocrine-mediated tumors in rats are species-specific and are not relevant for the use of the drug in humans.
Reproduction: Reproduction studies have been performed in rats and rabbits at parenteral doses of up to 1 mg/kg body weight per day. Some retardation of the physiological growth was noted in the offspring of rats which was transient and most likely attributable to GH inhibition brought about by excessive pharmacodynamic activity. There was no evidence of teratogenic, embryo/fetal or other reproduction effects due to octreotide.
MedsGo Class
Trophic Hormones & Related Synthetic Drugs / Other Gastrointestinal Drugs
Features
Brand
Sandostatin
Full Details
Dosage Strength
100 mcg / ml
Drug Ingredients
- Octreotide Acetate
Drug Packaging
Solution for Injection 1ml x 1's
Generic Name
Octreotide Acetate
Dosage Form
Solution for SC Injection
Registration Number
DR-XY18027
Drug Classification
Prescription Drug (RX)