Octreotide (Solution) Instructions for Use

ATC Code

H01CB02 (Octreotide)

Active Substance

Octreotide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Somatostatin analogue. A drug for intensive care in gastroenterology

Pharmacotherapeutic Group

Pituitary and hypothalamic hormones and their analogues; hypothalamic hormones; somatostatin and its analogues

Pharmacological Action

Octreotide is a synthetic analogue of somatostatin, which is a derivative of the natural hormone somatostatin and has similar pharmacological effects but a significantly longer duration of action. Octreotide suppresses the secretion of growth hormone (GH), both pathologically elevated and induced by arginine, physical exercise, and insulin-induced hypoglycemia. The drug also suppresses the secretion of insulin, glucagon, gastrin, serotonin, both pathologically elevated and induced by food intake; it also suppresses insulin and glucagon secretion stimulated by arginine. Octreotide suppresses the secretion of thyrotropin induced by thyrotropin-releasing hormone.

Unlike somatostatin, Octreotide suppresses GH secretion to a greater extent than insulin secretion, and its administration is not accompanied by subsequent hypersecretion of hormones (for example, GH in patients with acromegaly).

In patients with acromegaly, Octreotide reduces the concentration of GH and insulin-like growth factor-1 (IGF-1) in blood plasma. A reduction in GH concentration by 50% or more is noted in 90% of patients, with a GH concentration value of no more than 5 ng/mL achieved in approximately half of the patients. In most patients with acromegaly, Octreotide reduces the severity of headache, soft tissue swelling, hyperhidrosis, joint pain, and paresthesia. In patients with large pituitary adenomas, treatment with octreotide may lead to some reduction in tumor size.

In secreting tumors of the gastroenteropancreatic endocrine system, in cases of insufficient effectiveness of the therapy performed (surgical intervention, hepatic artery embolization, chemotherapy, including with streptozotocin and fluorouracil), the administration of octreotide may lead to an improvement in the course of the disease. Thus, in carcinoid tumors, the use of octreotide may lead to a reduction in the severity of flushing sensations and diarrhea, which in many cases is accompanied by a decrease in plasma serotonin concentration and urinary excretion of 5-hydroxyindoleacetic acid. In tumors characterized by hypersecretion of vasoactive intestinal peptide (VIPomas), the use of octreotide leads in most patients to a reduction in severe secretory diarrhea and, accordingly, to an improvement in the patient’s quality of life. Simultaneously, there is a reduction in associated electrolyte balance disorders, for example, hypokalemia, which allows for the discontinuation of enteral and parenteral administration of fluids and electrolytes. In some patients, tumor progression slows down or stops, and the size of the tumor itself, as well as liver metastases, decreases. Clinical improvement is usually accompanied by a decrease in the plasma concentration of vasoactive intestinal peptide (VIP) or its normalization. In glucagonomas, the use of octreotide leads to a reduction in necrolytic migratory erythema. Octreotide does not have any significant effect on the severity of hyperglycemia in diabetes mellitus, while the need for insulin or oral hypoglycemic drugs usually remains unchanged. The drug causes a reduction in diarrhea, which is accompanied by weight gain. Although the reduction in plasma glucagon concentration under the influence of octreotide is transient, clinical improvement remains stable throughout the entire period of drug use. In patients with gastrinomas/Zollinger-Ellison syndrome, when using octreotide as monotherapy or in combination with proton pump inhibitors or H₂-histamine receptor blockers, it is possible to reduce gastric hydrochloric acid hypersecretion, reduce plasma gastrin concentration, and reduce the severity of diarrhea and flushing. In patients with insulinomas, Octreotide reduces the level of immunoreactive insulin in the blood (this effect may be short-term – about 2 hours). In patients with operable tumors, Octreotide can ensure the restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, glycemic control may improve without a simultaneous prolonged decrease in blood insulin levels.

In patients with rare tumors that hypersecrete growth hormone-releasing factor (somatoliberinomas), Octreotide reduces the severity of acromegaly symptoms. This is associated with the suppression of growth hormone-releasing factor and growth hormone itself secretion. Subsequently, pituitary hypertrophy may decrease.

In bleeding from esophageal and gastric varices in patients with liver cirrhosis, the use of octreotide in combination with specific treatment (for example, sclerotherapy) leads to more effective control of bleeding and early rebleeding, reduces the volume of transfusions, and improves 5-day survival. It is believed that the mechanism of action of octreotide is associated with a reduction in organ blood flow by suppressing vasoactive hormones such as VIP and glucagon.

Pharmacokinetics

Absorption

After subcutaneous administration, Octreotide is rapidly and completely absorbed. C_max of octreotide in plasma is reached within 30 minutes.

Distribution

Binding to plasma proteins is 65%. The binding of octreotide to blood cells is extremely insignificant. V_d is 0.27 L/kg.

Elimination

T_1/2 after subcutaneous administration of octreotide is 100 minutes. After intravenous administration, the elimination of octreotide occurs in 2 phases, with T_1/2 of 10 and 90 minutes, respectively. Most of the octreotide is excreted through the intestines, about 32% is excreted unchanged by the kidneys. Total clearance is 160 mL/min.

Indications

Acromegaly: for controlling the main manifestations of the disease and reducing the level of GH and IGF-1 in plasma in cases where there is insufficient effect from surgical treatment or radiation therapy. Octreotide is also indicated for the treatment of patients with acromegaly who have refused surgery or have contraindications to it, as well as for short-term treatment in the intervals between courses of radiation therapy until its effect fully develops.

Secreting endocrine tumors of the gastrointestinal tract and pancreas – for symptom control

• Carcinoid tumors with carcinoid syndrome;
• VIPomas;
• Glucagonomas;
• Gastrinomas/Zollinger-Ellison syndrome – usually in combination with proton pump inhibitors and H₂-histamine receptor blockers;
• Insulinomas (for controlling hypoglycemia in the preoperative period, as well as for maintenance therapy);
• Somatoliberinomas (tumors characterized by hypersecretion of growth hormone-releasing factor).

The drug is not an antitumor drug and its use cannot lead to a cure for this category of patients.

Control of bleeding and prevention of recurrent bleeding from esophageal and gastric varices in patients with liver cirrhosis. Octreotide is used in combination with specific therapeutic measures, for example, endoscopic sclerotherapy.

ICD codes

Dosage Regimen

Solution

Subcutaneously, intravenously by infusion.

For acromegaly – subcutaneously, at a dose of 300 mcg at 8 or 12-hour intervals. This dose is used in case of ineffectiveness of initial therapy (the drug Octreotide, solution for intravenous and subcutaneous administration, 50-100 mcg at 8 or 12-hour intervals). The ineffectiveness of initial therapy is assessed based on monthly determinations of blood GH concentration (target concentration: GH < 2.5 ng/mL; IGF-1 within normal limits), analysis of clinical symptoms, and drug tolerance. If the 300 mcg dose is ineffective, it is recommended to adjust the dose based on the above criteria. The maximum dose of 1500 mcg/day should not be exceeded.

In patients receiving Octreotide at a stable dose, GH concentration should be determined every 6 months. If after three months of treatment with octreotide there is no sufficient reduction in GH concentration and improvement in the clinical picture of the disease, therapy should be discontinued.

For tumors of the gastroenteropancreatic endocrine system: subcutaneously, at a dose of 300 mcg 1-2 times/day. This dose is used in case of ineffectiveness of initial therapy (the drug Octreotide, solution for intravenous and subcutaneous administration, 50 mcg 1-2 times/day with a gradual increase to 100-200 mcg 3 times/day). The ineffectiveness of initial therapy is assessed based on the achieved clinical effect, impact on the concentration of hormones produced by the tumor (in the case of carcinoid tumors – impact on the urinary excretion of 5-hydroxyindoleacetic acid), and tolerance. In exceptional cases, it is permissible to prescribe a dose exceeding 600 mcg/day to the patient; the drug dose can be gradually increased to 300-600 mcg 3 times/day. Maintenance doses of the drug should be selected individually. For carcinoid tumors, if therapy with octreotide at the maximum tolerated dose for 1 week was not effective, treatment should not be continued.

For bleeding from esophageal and gastric varices intravenous infusion at a rate of 25 mcg/hour for 5 days.

Use in specific patient groups

Currently, there are no data indicating that elderly patients have reduced tolerance to octreotide and require a change in the dosing regimen.

Adjustment of the maintenance dose is recommended in patients with impaired liver function.

In patients with impaired renal function, no adjustment of the octreotide dosing regimen is required.

Experience with the use of octreotide in children is limited.

Rules for using the drug

Subcutaneous administration

Patients who self-administer octreotide subcutaneously should receive detailed instructions from a doctor or nurse.

Before administration, the solution should be warmed to room temperature – this helps reduce discomfort at the injection site. The drug should not be injected into the same site at short intervals. Ampoules should be opened immediately before administration of the drug; unused amount of solution should be discarded.

Intravenous infusion administration

If intravenous infusion of octreotide is necessary, the contents of one ampoule containing 600 mcg of active substance should be diluted in 60 mL of 0.9% sodium chloride solution. Octreotide at temperatures below 25°C (77°F) maintains physical and chemical stability for 24 hours in sterile 0.9% sodium chloride solution or 5% dextrose solution in water. However, since Octreotide can affect glucose metabolism, it is preferable to use 0.9% sodium chloride solution. Before intravenous administration, the ampoule should be carefully inspected for changes in solution color and the presence of foreign particles.

To avoid microbial contamination, diluted solutions should be used immediately after preparation. If the solution is not used immediately, it should be stored at a temperature of 2-8°C (46.4°F). Before administration, the solution should be warmed to room temperature. The total time between dilution, refrigeration storage, and completion of solution administration should not exceed 24 hours.

Adverse Reactions

The main undesirable phenomena noted during the use of octreotide were side effects from the digestive, nervous, hepatobiliary systems, as well as metabolic disorders and the development of nutritional deficiencies.

In clinical studies, the most frequently observed events when prescribing the drug were diarrhea, abdominal pain, nausea, flatulence, headache, gallstone formation, hyperglycemia, and constipation. Dizziness, pain of various localization, impaired colloidal stability of bile (formation of cholesterol microcrystals), thyroid dysfunction (decreased levels of thyroid-stimulating hormone, total and free thyroxine), loose stools, decreased glucose tolerance, vomiting, asthenia, and hypoglycemia were also frequently reported.

In rare cases, when using the drug, phenomena resembling acute intestinal obstruction may occur: progressive abdominal distension, severe pain in the epigastric region, abdominal wall tension, muscular defense.

Although fecal fat excretion may increase, to date there is no evidence that long-term treatment with octreotide can lead to the development of nutritional deficiency due to malabsorption.

There have been very rare reports of acute pancreatitis developing within the first hours or days of subcutaneous use of octreotide and disappearing after drug withdrawal. Furthermore, with long-term subcutaneous use of octreotide, cases of pancreatitis associated with cholelithiasis have been noted.

According to ECG studies during the use of the drug in patients with acromegaly and carcinoid syndrome: QT interval prolongation, electrical axis deviation, early repolarization, low-voltage ECG pattern, shift of the transition zone, early P wave, and nonspecific ST segment and T wave changes were observed. Since this category of patients has heart disease, a causal relationship between the use of octreotide and the development of these adverse events has not been established.

The following criteria were used to determine the frequency of adverse reactions identified during clinical studies of the drug: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (< 1/10000), including isolated reports.

From the digestive system: very common – diarrhea, abdominal pain, nausea, constipation, flatulence; common – dyspeptic disorders, vomiting, feeling of fullness/heaviness in the abdomen, steatorrhea, loose stools, change in stool color, anorexia.

From the nervous system: very common – headache; common – dizziness.

From the endocrine system: very common – hyperglycemia; common – hypothyroidism/thyroid dysfunction (decreased levels of thyroid-stimulating hormone, total and free thyroxine); hypoglycemia, impaired glucose tolerance.

From the hepatobiliary system: very common – cholelithiasis, i.e., gallstone formation; common – cholecystitis, impaired colloidal stability of bile (formation of cholesterol microcrystals), hyperbilirubinemia, increased activity of liver transaminases.

Dermatological reactions: common – pruritus, rash, hair loss.

From the respiratory system: common – dyspnea.

From the cardiovascular system: common – bradycardia; uncommon – tachycardia.

General disorders and administration site conditions: very common – injection site pain; uncommon – dehydration.

During therapy with octreotide in clinical practice, the following undesirable phenomena have been noted regardless of the presence of a causal relationship with the use of the drug:

From the immune system: anaphylactic reactions, allergic reactions/hypersensitivity.

Dermatological reactions: urticaria.

From the hepatobiliary system: acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, increased levels of alkaline phosphatase, gamma-glutamyltransferase.

From the cardiovascular system: arrhythmias.

Contraindications

• Hypersensitivity to octreotide or other components of the drug;
• Children under 18 years of age.

With caution cholelithiasis (gallstone disease); diabetes mellitus

Use in Pregnancy and Lactation

Experience with the use of octreotide in pregnant women is limited. The drug Octreotide should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

It is not known whether the drug passes into breast milk, therefore, when using the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Adjustment of the maintenance dose is recommended in patients with impaired liver function.

Use in Renal Impairment

In patients with impaired renal function, no adjustment of the octreotide dosing regimen is required.

Pediatric Use

Experience with the use of octreotide in children is limited.

Geriatric Use

Currently, there are no data indicating that elderly patients have reduced tolerance to octreotide and require a change in the dosing regimen.

Special Precautions

In pituitary tumors secreting GH, patients receiving Octreotide must be carefully monitored, as an increase in tumor size with the development of such a serious complication as visual field narrowing is possible. In these cases, the need for other treatment methods should be considered.

Since a decrease in growth hormone levels and normalization of insulin-like growth factor-1 levels during therapy with octreotide may lead to the restoration of fertility in women with acromegaly, when using the drug, women of childbearing age should use reliable methods of contraception.

When prescribing octreotide for a long period, it is necessary to monitor thyroid function.

In case of bradycardia development during octreotide use, if necessary, it is possible to reduce the doses of beta-blockers, calcium channel blockers, or drugs affecting water-electrolyte balance.

In some patients, Octreotide may alter the absorption of fats in the intestine.

During octreotide use, a decrease in cobalamin (vitamin B₁₂) levels and deviations from the norm in the cobalamin absorption test (Schilling test) were noted.

When using octreotide in patients with a history of vitamin B₁₂ deficiency, it is recommended to monitor cobalamin levels in the body.

Before prescribing octreotide, patients should undergo a baseline ultrasound examination of the gallbladder.

During treatment with Octreotide, repeated ultrasound examinations of the gallbladder should be performed, preferably at 6-12 month intervals.

If gallstones are detected before starting treatment, the potential benefits of octreotide therapy should be weighed against the possible risk associated with their presence. There is no data on any negative effect of octreotide on the course or prognosis of pre-existing cholelithiasis.

Asymptomatic gallstones. Octreotide use can be discontinued or continued – according to the benefit/risk assessment. In any case, there is no need to take any action other than continued monitoring, making it more frequent if necessary.

Symptomatic gallstones. Octreotide use can be discontinued or continued – according to the benefit/risk assessment. In any case, the patient should be treated as in other cases of symptomatic cholelithiasis. Drug treatment includes the use of combinations of bile acid preparations (for example, chenodeoxycholic acid at a dose of 7.5 mg/kg per day in combination with ursodeoxycholic acid at the same dose) under ultrasound control – until the stones completely disappear.

When treating gastrointestinal and pancreatic endocrine tumors with octreotide, a sudden recurrence of disease symptoms may occur in rare cases.

In patients with insulinomas during octreotide treatment, an increase in the severity and duration of hypoglycemia may be noted (this is associated with a more pronounced suppressive effect on GH and glucagon secretion than on insulin secretion, as well as with a shorter duration of the inhibitory effect on insulin secretion). Careful regular monitoring of these patients should be ensured both at the beginning of treatment with Octreotide and with each change in the drug dose. Significant fluctuations in blood glucose concentration can be attempted to be reduced by more frequent administration of octreotide in smaller doses. In patients with type 1 diabetes mellitus, Octreotide may reduce the need for insulin. In patients without diabetes and with type 2 diabetes with partially preserved insulin secretion, octreotide administration may lead to postprandial hyperglycemia. When using octreotide in patients with diabetes mellitus, it is recommended to monitor blood glucose concentration and adjust antidiabetic therapy.

Since after bleeding from varicose veins of the esophagus and stomach there is an increased risk of developing type 1 diabetes mellitus, and in patients suffering from diabetes mellitus, changes in insulin requirements are also possible, in these cases systematic monitoring of blood glucose concentration is necessary.

Adjustment of the dosing regimen of concurrently used diuretics, beta-blockers, “slow” calcium channel blockers, insulin, oral hypoglycemic agents, glucagon is necessary.

Effect on the ability to drive vehicles and mechanisms

Some side effects of octreotide may negatively affect the ability to drive vehicles and other mechanisms requiring increased concentration and speed of psychomotor reactions. In this regard, it is recommended that if these symptoms appear, caution should be exercised when driving vehicles or mechanisms requiring increased concentration.

Overdose

Isolated cases of octreotide overdose in children and adults in clinical practice have been reported. With accidental use of octreotide in adults at a dose of 2400-6000 mcg/day, administered intravenously by drip (infusion rate of 100-250 mcg/hour) or subcutaneously (1500 mcg 3 times/day), the following were observed: development of arrhythmias, decreased blood pressure, sudden cardiac arrest, cerebral hypoxia, pancreatitis, fatty liver degeneration, diarrhea, weakness, lethargy, weight loss, hepatomegaly and lactic acidosis.

With accidental use of octreotide in children at a dose of 50-3000 mcg/day, administered intravenously by drip (infusion rate of 2.1-500 mcg/hour) or subcutaneously (50-100 mcg), only moderate hyperglycemia was noted.

With subcutaneous administration of octreotide at a dose of 3000-30000 mcg/day (divided into several administrations) in patients with tumors, no new adverse events (other than those indicated in the “Adverse Reactions” section) were identified.

Drug Interactions

Pharmacokinetic interaction

Reduces the absorption of cyclosporine, slows down the absorption of cimetidine. Adjustment of the dosing regimen of concurrently used diuretics, beta-blockers, “slow” calcium channel blockers, oral hypoglycemic drugs, glucagon is necessary.

Concomitant use of octreotide and bromocriptine increases the bioavailability of bromocriptine.

Reduces the metabolism of substances metabolized with the participation of cytochrome P450 enzyme system enzymes (may be due to suppression of GH). Since such effects of octreotide cannot be excluded, caution should be exercised when prescribing drugs metabolized by the cytochrome P450 system and having a narrow therapeutic range (for example, quinidine, terfenadine).

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature of 8 to 25°C (77°F).

Shelf Life

Shelf life – 5 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.