Octreotide

Pharmacological properties

octra is a synthetic octapeptide that is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a significantly longer duration of action. the drug inhibits pathologically increased secretion of growth hormone, as well as peptides and serotonin, which are produced in the gastroenteropancreatic endocrine system.

In healthy individuals, octreotide inhibits: secretion of growth hormone, which is stimulated by arginine, exercise and insulin hypoglycemia; the secretion of insulin, glucagon, gastrin and other peptides of the gastroenteropancreatic endocrine system, which is stimulated by food intake, as well as the secretion of insulin and glucagon, which is stimulated by arginine; secretion of thyrotropin, which is stimulated by thyroliberin. Unlike somatostatin, octreotide inhibits growth hormone more than insulin, its administration is not accompanied by ricochet hypersecretion of hormones (that is, growth hormone in patients with acromegaly).

In patients with acromegaly, octreotide reduces the concentration of growth hormone and insulin-like growth factor 1 (IGF-1) in blood plasma. Inhibition of growth hormone by 50% or more is noted in 90% of patients; a decrease in plasma growth hormone levels of 5 ng / ml is achieved in approximately half of the patients. In most patients with acromegaly, octreotide significantly reduces the severity of symptoms such as headache, swelling of the skin and soft tissues, hyperhidrosis, joint pain and paresthesia. In patients with large pituitary adenomas, treatment with octreotide can lead to a decrease in tumor size.

In patients with functional endocrine tumors of the gastrointestinal tract and pancreas, octreotide, due to its various endocrine effects, affects a number of clinical signs of the disease. Clinical and symptomatic improvement is noted in patients who still have symptoms associated with the tumor, despite previous treatment, which may include surgical treatments, hepatic artery embolization, and a variety of chemotherapy, such as streptozotocin and fluorouracil.

In carcinoid tumors, the use of octreotide can lead to a decrease in the severity of symptoms such as a feeling of flushing and diarrhea, which in many cases is accompanied by a decrease in serotonin concentration in the blood plasma and excretion of 5-hydroxyindoleacetic acid in the urine.

In tumors characterized by hyperproduction of a vasoactive intestinal peptide (VIP), the use of octreotide in most patients leads to a decrease in severe secretory diarrhea, which is characteristic of this condition, which, in turn, improves the patients quality of life. At the same time, there is a decrease in concomitant disturbances in the electrolyte balance, for example, hypokalemia, which makes it possible to cancel the enteral and parenteral administration of fluid and electrolytes. In some patients, there is a slowdown or arrest of tumor growth and even a decrease in its size, especially liver metastases. Clinical improvement is usually accompanied by a decrease (even to normal values) in the concentration of VIP in blood plasma.

With glucagonomas, the use of octreotide in most cases leads to a noticeable decrease in necrotizing migratory eruptions, which are characteristic of this condition. Octreotide does not show any significant effect on mild diabetes mellitus, which is often noted with glucagonomas, and usually does not reduce the need for insulin or oral hypoglycemic drugs. In patients with diarrhea, octreotide contributes to its reduction, which is accompanied by an increase in body weight. With the use of octreotide, a rapid decrease in the concentration of glucagon in the blood plasma is often noted, however, with prolonged treatment, this effect does not persist.At the same time, symptomatic improvement remains stable for a long time.

For gastrinomas / Zollinger-Ellison syndrome, octreotide, used as monotherapy or in combination with proton pump inhibitors or H antagonists₂receptors, can reduce the secretion of acid in the stomach and lead to clinical improvement, including regarding diarrhea. It is also possible to reduce the severity and other symptoms, obviously associated with the synthesis of peptides by the tumor, including hot flashes. In some cases, there is a decrease in the concentration of gastrin in the blood plasma.

In patients with insulinomas, octreotide reduces the level of immunoreactive insulin in the blood. This effect, however, can 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 can improve without a simultaneous long-term decrease in insulin levels in the blood.

In patients with tumors producing RF growth hormone (somatoliberinomas), octreotide reduces the severity of acromegaly symptoms. This, obviously, is associated with inhibition of the secretion of RF growth hormone and growth hormone itself. In the future, pituitary hypertrophy may decrease.

With refractory diarrhea in patients with acquired immunodeficiency syndrome (AIDS), the use of octreotide leads to complete or partial normalization of stool in approximately ¹/₃ patients with diarrhea that is not controlled by adequate antimicrobial and / or antidiarrheal therapy.

In patients undergoing pancreatic surgery, the use of octreotide during and after surgery reduces the incidence of typical postoperative complications (e.g., pancreatic fistulas, abscesses, sepsis, postoperative acute pancreatitis).

When bleeding from varicose veins of the esophagus and stomach in patients with cirrhosis of the liver, the use of octreotide in combination with specific treatment (for example, sclerotherapy) led to a more effective stop of bleeding and the prevention of early repeated bleeding, a decrease in the volume of transfusions and an improvement in 5-day survival. Although the mechanism of action of octreotide is not precisely established, it is believed that the drug reduces organ blood flow by inhibiting vasoactive hormones such as VIP and glucagon.

Pharmacokinetics After sc administration, octreotide is rapidly and completely absorbed. WITH_max drug in blood plasma is reached within 30 minutes Binding to plasma proteins is 65%. The binding of octreotide to blood cells is extremely negligible. Distribution volume - 0.27 l / kg. The total clearance is 160 ml / min. T_½ after s / c injection of the drug - 100 minutes After iv administration, the drug is excreted in two phases with T_½ 10 and 90 min, respectively. Most of the administered dose of the peptide is excreted in the feces, about 32% - unchanged in the urine. Impaired renal function does not affect the total exposure (AUC) of octreotide administered sc. The ability to eliminate can be reduced in patients with cirrhosis.

Indications

• Acromegaly - to control the main manifestations of the disease and reduce the levels of growth hormone and IGF-1 in blood plasma in cases where there is no sufficient effect from surgical treatment and radiation therapy. the drug 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 is fully developed. a decrease in the severity of symptoms associated with endocrine tumors of the gastrointestinal tract and pancreas: carcinoid tumors with the presence of carcinoid syndrome; vipomas (tumors characterized by hyperproduction of vip); glucagonomas; gastrinomas / Zollinger-Ellison syndrome - usually in combination with histamine H2 receptor antagonists or proton pump inhibitors; insulinomas (to control hypoglycemia in the preoperative period, as well as for maintenance therapy); somatoliberinomas (tumors characterized by overproduction of rf growth hormone).octra is not an antitumor drug and its use cannot lead to the cure of this category of patients. refractory diarrhea in AIDS patients. prevention of complications after pancreatic surgery. stopping bleeding and preventing recurrence of bleeding from varicose veins of the esophagus in patients with cirrhosis of the liver (in combination with specific therapeutic measures, for example, with endoscopic sclerotherapy).

Application

The drug is administered sc or iv.

With acromegaly, the drug is first administered at 0.05–0.1 mg (0.5–1 ml) sc at intervals of 8 or 12 hours. Further, the dose depends on the concentration of growth hormone and IGF-1 in the blood (target concentration of hormones in the blood are: growth hormone - 2.5 ng / ml, IGF-1 - within normal limits), drug tolerance and clinical effect. For most patients, the optimal daily dose is 0.3 mg. The maximum daily dose is 1.5 mg / day, which should not be exceeded.

If within 3 months of treatment with Octra, a sufficient decrease in the level of growth hormone and improvement of the clinical picture of the disease is not observed, therapy should be discontinued.

In endocrine tumors of the gastrointestinal tract and pancreas, the drug is administered subcutaneously in an initial dose of 0.05 mg (0.5 ml) 1-2 times a day. Subsequently, depending on the achieved clinical effect, the effect on the level of hormones produced by the tumor (in the case of carcinoid tumors, the effect on the excretion of 5-hydroxyindoleacetic acid in the urine) and the tolerability of the drug, the dose can be gradually increased to 0.1-0.2 mg 3 times per day. In exceptional cases, higher doses may be needed. The maintenance dose of the drug should be selected individually. If within 1 week of treatment with Octra at the maximum tolerated dose, improvement does not occur, therapy should be discontinued.

With refractory diarrhea in patients with AIDS, the drug is administered subcutaneously in an initial dose of 0.1 mg 3 times a day. If diarrhea does not stop after a week of treatment, the dose should be increased individually, even to 0.25 mg (2.5 ml) 3 times a day. Dose adjustment is carried out taking into account the clinical effect and tolerability of the drug. If within 1 week of treatment with Octra at a dose of 0.25 mg (2.5 ml) 3 times a day, improvement does not occur, therapy should be discontinued.

To prevent complications after pancreatic surgery, the drug is administered s.c. 0.1 mg 3 times a day for the next 7 days, starting from the day of surgery (no later than 1 hour before laparotomy).

When bleeding from varicose veins of the esophagus, the drug is administered at a dose of 25 μg / h by continuous IV infusion for 5 days. Octra can be diluted with 0.9% solution of sodium chloride.

Patients with cirrhosis of the liver noted a good tolerance to the drug, which was used for 5 days in doses of up to 50 μg / h in the form of a continuous IV infusion due to bleeding from varicose veins of the esophagus.

Contraindications

Known hypersensitivity to octreotide or other components of the drug.

Side effects

Adverse reactions are distributed according to the frequency of occurrence: very often (≥1 / 10); often (≥1 / 100, 1/10); infrequently (≥1 / 1000, 1/100); rarely (≥1 / 10,000, 1/1000); very rarely (1/10 000), including single messages.

Digestive system disorders: very often - diarrhea, abdominal pain, nausea, flatulence, cholelithiasis; often - dyspepsia, vomiting, bloating, steatorrhea, frequent loose stools, discoloration of feces, cholecystitis, the formation of bile stones, hyperbilirubinemia; in some cases, progressive bloating, severe pain in the epigastric region, abdominal pain and muscle tension; the frequency has not been established - acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis. Cholestasis, jaundice, cholestatic jaundice.

Side effects from the gastrointestinal tract can be reduced if you do not eat food before or immediately after sc administration of octreotide, it is recommended to introduce the drug between meals or at bedtime.

Disorders from the central nervous system: very often - headache; often - dizziness, asthenia.

Disorders from the endocrine system: often - hypothyroidism, thyroid gland dysfunction (for example, a decreased level of thyroid stimulating hormone, a reduced level of total T₄reduced free T₄).

Metabolic disorders: very often - hyperglycemia; often - hypoglycemia, impaired glucose tolerance, anorexia; infrequently - dehydration.

General disorders and disorders at the injection site: very often - pain at the injection site. Pain or sensation of acute pain, tingling or burning at the injection site with redness and swelling rarely lasts longer than 15 minutes. Local discomfort can be reduced by warming the solution before injection to room temperature, or by introducing a smaller volume of more concentrated solution.

Laboratory studies: often - increased levels of transaminases; frequency not established - increased levels of alkaline phosphatase, increased levels of gamma-glutamyl transferase.

Violation of the skin and subcutaneous tissue: often - itching, rash, alopecia; frequency not established - urticaria.

Violations of the respiratory system: often - dyspnea.

Disorders from the cardiovascular system: often - bradycardia; infrequently - tachycardia; frequency not established - arrhythmia. In patients with acromegaly and carcinoid syndrome, ECG changes such as lengthening of the Q – T interval, axis displacement, early repolarization, low voltage, R / S transition, early increase in the R wave, nonspecific ST – T wave changes were noted. The relationship between these phenomena and the use of octreotide has not been established, since many of these patients have underlying cardiac disease (see SPECIAL INSTRUCTIONS).

Immune system disorders: hypersensitivity reactions, anaphylaxis.

special instructions

S / c introduction. Patients who administer the drug themselves by SC injection should receive precise instructions from a doctor or nurse.

To reduce discomfort at the injection site, it is recommended to bring the temperature of the solution to room temperature before injection. Repeated injections at the same site should be avoided after a short period of time.

Ampoules should be opened only before administration, the remains of the drug should be disposed of.

In / in infusion. The diluted solution remains physically and chemically stable for at least 24 hours at a temperature of no higher than 25 ° C.

Are common. Since sometimes pituitary tumors secreting growth hormone can grow, causing serious complications (for example, narrowing of the visual field), careful monitoring of the condition of all patients is essential. In case of signs of tumor enlargement, the need for alternative treatments should be considered.

Due to the therapeutic benefits of lowering growth hormone levels and normalizing the concentration of IGF-1 in women with acromegaly, fertility can potentially be restored. During treatment with octreotide, women of reproductive age should be advised to use adequate methods of contraception.

In patients taking octreotide therapy for a long time, thyroid function should be monitored.

The phenomena associated with the cardiovascular system. Cases of bradycardia have been infrequently reported. Dose adjustment may be necessary for drugs such as β-adrenergic blockers, calcium channel blockers, drugs that control fluid balance or electrolyte balance.

Phenomenon associated with the gallbladder. In 15-30% of patients receiving octreotide s / c for a long time, the formation of stones in the gall bladder is noted.In most cases, gallstones were not accompanied by symptoms. In this regard, it is recommended to conduct an ultrasound of the gallbladder before starting therapy with Octra and every 6-12 months of treatment. With clinical manifestations, gallstone disease should be treated either by the use of bile acids that dissolve stones, or by surgical methods.

Tumors of the gastroenteropancreatic endocrine system. During the treatment of tumors of the gastroenteropancreatic endocrine system, the symptomatic control of the Octra may occasionally suddenly be lost, which is accompanied by the rapid return of severe symptoms.

Glucose metabolism. Octreotide inhibits the secretion of growth hormone, glucagon and insulin. Therefore, glucose tolerance after eating may be impaired and, in some cases, persistent hyperglycemia may occur due to prolonged administration of the drug.

In patients with insulinomas, the intensity and duration of hypoglycemia may increase. These patients require close monitoring, especially at the beginning of Octra therapy and during each dose change. Obvious fluctuations in blood glucose concentration can be reduced due to the more frequent administration of low doses.

In patients with type I diabetes, the dose of insulin can be reduced. In patients without and with type II diabetes mellitus with a partially intact reserve of insulin, administration of Octra can lead to an increase in glycemia after eating. Careful monitoring of glucose tolerance and antidiabetic treatment are recommended.

Varicose veins of the esophagus. Because episodes of bleeding from varicose veins of the esophagus are associated with an increased risk of developing insulin-dependent diabetes or a change in the history of insulin in patients with diabetes mellitus, proper monitoring of blood glucose levels is necessary.

Local reactions. There are no reports of tumors at the injection site in patients receiving octreotide treatment for up to 15 years.

Trophic. In some patients, octreotide may interfere with fat absorption.

Some patients have reduced vitamin B levels.₁₂ and abnormal Schilling test results. In patients with vitamin B vitamin deficiency₁₂ history should monitor the level of this vitamin during therapy with Octra.

Elderly patients. There is no evidence of the need for dose adjustment in elderly patients.

Patients with impaired liver function. In patients with cirrhosis of the liver T_½ the drug may increase, which requires correction of the maintenance dose.

Patients with impaired renal function. In case of impaired renal function, it is not necessary to adjust the dose of octreotide, which is administered s.c.

Use during pregnancy and lactation. The possibility of using octreotide in pregnant women has not been studied, therefore, during pregnancy, Octra is prescribed only for health reasons.

It is not known whether octreotide passes into breast milk. If it is necessary to use the drug by breast-feeding women, it is necessary to stop breastfeeding.

Children. Taking Octra is contraindicated in children because of a lack of data regarding the use of octreotide in pediatric practice.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Considering that in sensitive patients, when using the drug, adverse reactions (dizziness, etc.) may occur, while taking the drug should refrain from driving vehicles and performing other work requiring attention.

Interactions

It was found that octreotide reduces the absorption of cyclosporine in the intestine and slows down the absorption of cimetidine.

The simultaneous administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.Somatostatin analogs can reduce the metabolic clearance of substances that are metabolized with the participation of cytochrome P450 enzymes, which may be due to inhibition of growth hormone secretion, therefore, other drugs that are metabolized mainly with the participation of CYP 3A4, as well as with a narrow therapeutic index, should be used with caution quinidine, terfenadine).

Octreotide acetate is unstable in solutions for complete parenteral nutrition. Do not use solvents not specified in the APPLICATION section.

Overdose

Symptoms: arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, steatosis, diarrhea, weakness, drowsiness, weight loss, hepatomegaly and milk acidosis, hyperglycemia.

The treatment is symptomatic.

Storage conditions

In the dark place at a temperature of 2-8 ° C. do not freeze.