Sandostatin solution for injection 0.1 mg ampoule 1 ml No. 5

Pharmacological properties

Pharmacodynamics. Sandostatin is a synthetic octapeptide, a derivative of the natural hormone somatostatin, it has similar pharmacological effects, but a much longer duration of action. The drug inhibits pathologically increased secretion of growth hormone, as well as peptides and serotonin produced in the gastroenteropancreatic endocrine system.

In animals, octreotide is a more potent inhibitor of growth hormone, glucagon, and insulin release than somatostatin, with greater selectivity for growth hormone and glucagon.

In healthy individuals, Sandostatin, like somatostatin, inhibits:

Unlike somatostatin, octreotide inhibits growth hormone more than insulin, and its administration is not accompanied by rebound hypersecretion of hormones (i.e., growth hormone in patients with acromegaly).

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

In patients with acromegaly, Sandostatin reduces the concentration of growth hormone and insulin-like growth factor-1 (IGF-1) in the blood plasma of most patients. Suppression of growth hormone by 50% or more is noted in 90% of patients, a decrease in the level of growth hormone in the blood plasma of 5 ng / ml is achieved in approximately 50% of patients. In most patients with acromegaly, Sandostatin noticeably reduces the severity of symptoms such as headache, hyperhidrosis, fatigue, joint pain, paresthesia and carpal tunnel syndrome. In patients with pituitary adenomas secreting growth hormone, treatment with Sandostatin may lead to some reduction in tumor size.

In patients with functional endocrine tumors of the gastrointestinal tract and pancreas, Sandostatin provides continuous control of symptoms related to the underlying disease. The effects of octreotide in various types of gastroenteropancreatic tumors are listed below. Clinical and symptomatic improvement is observed in patients with tumor-related symptoms despite previous treatment, including surgery, hepatic artery embolization, and various chemotherapy, such as streptozocin and fluorouracil.

In carcinoid tumors, the use of Sandostatin may reduce the severity of symptoms such as hot flashes and diarrhea, which in many cases is accompanied by a decrease in plasma serotonin concentration and a decrease in urinary excretion of 5-hydroxyindoleacetic acid.

In tumors characterized by hyperproduction of vasoactive intestinal peptide (VIP), the use of Sandostatin in most patients leads to a decrease in the severity of secretory diarrhea characteristic of this condition, which, in turn, improves the patient's quality of life. At the same time, the number of concomitant electrolyte imbalances, such as hypokalemia, decreases, which allows for the abolition of enteral and parenteral administration of fluids and electrolytes. In some patients, a slowdown or cessation of tumor progression and even a decrease in its size, especially liver metastases, are noted. Clinical improvement is usually accompanied by a decrease (to normal values) in the concentration of VIP in the blood plasma.

In glucagonomas, the use of Sandostatin in most cases leads to a marked reduction in the severity of the necrotizing migratory rash characteristic of this condition. Sandostatin does not have any significant effect on the severity of mild diabetes mellitus, which is often observed in glucagonomas, and usually does not lead to a decrease in the need for insulin or oral hypoglycemic drugs. In patients with diarrhea, Sandostatin causes a decrease in its severity, which is accompanied by an increase in body weight. When using Sandostatin, a rapid decrease in the concentration of glucagon in the blood plasma is often observed, but this effect is not maintained with prolonged treatment. At the same time, symptomatic improvement remains stable for a long time.

In gastrinomas/Zollinger-Ellison syndrome Sandostatin, used as monotherapy or in combination with proton pump inhibitors or H2-receptor antagonists, can reduce the production of hydrochloric acid in the stomach and cause clinical improvement, including diarrhea. It is also possible to reduce the severity of other symptoms, presumably caused by the synthesis of peptides by the tumor, including hot flashes. In some cases, a decrease in the concentration of gastrin in the blood plasma is noted.

In patients with growth hormone-releasing factor (GHRH)-overproducing tumors (GH-RH-overproducing tumors), Sandostatin reduces the severity of symptoms of acromegaly. This is probably due to suppression of GHRH secretion and growth hormone itself. Pituitary hypertrophy may subsequently be reduced.

In refractory diarrhea in AIDS patients, the use of Sandostatin leads to complete or partial normalization of stool in approximately 1/3 of patients with diarrhea not controlled by adequate therapy with antimicrobial and/or antidiarrheal agents.

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

In patients with esophageal and gastric variceal bleeding from cirrhosis, Sandostatin, in combination with specific treatment (e.g. sclerosing therapy), resulted in more effective control of bleeding and early rebleeding, reduced transfusion requirements and improved 5-day survival. Although the exact mechanism of action of Sandostatin is not known, it is thought to reduce organ blood flow by inhibiting vasoactive hormones such as VIP and glucagon.

Pharmacokinetics. Absorption. After s / c administration, Sandostatin is rapidly and completely absorbed. C max of the drug in blood plasma is reached after 30 minutes.

Distribution. Plasma protein binding is 65%. Binding of Sandostatin to formed blood cells is extremely low. The volume of distribution is 0.27 l/kg body weight.

Excretion. Total clearance - 160 ml/min. T ½ of the drug after s / c injection - 100 min. After i / v administration, the drug is excreted in two phases with T ½ 10 and 90 min, respectively. Most of the administered dose of peptide is excreted in feces, about 32% - unchanged in urine.

Impaired renal function does not affect the total exposure (AUC) of octreotide administered subcutaneously.

Hepatic impairment: Elimination capacity may be reduced by 30% in patients with cirrhosis.

Indication

Acromegaly: to control the main manifestations of the disease and reduce the level of growth hormone and insulin-like growth factor (IGF)-1 in the blood plasma in cases where there is no sufficient effect from surgical treatment and radiotherapy. Sandostatin is also indicated for the treatment of patients with acromegaly who have refused surgery or who have contraindications to it, as well as for short-term treatment in the intervals between courses of radiotherapy until its effect is fully manifested.

Reducing symptoms of endocrine tumors of the gastrointestinal tract and pancreas:

Sandostatin is not an anticancer drug, and its use cannot lead to a cure in this category of patients.

Prevention of complications after pancreatic surgery

Stopping bleeding and preventing recurrence of bleeding from esophageal varices in patients with liver cirrhosis (in combination with specific therapeutic measures, for example, endoscopic sclerosing therapy).

Application

In acromegaly, the drug is initially administered at 0.05-0.1 mg s / c 3 times a day. Subsequently, the dose is set on the basis of monthly determinations of the concentration of growth hormone and IGF-1 in the blood, analysis of clinical symptoms and tolerability of the drug (target concentrations of hormones in the blood are: growth hormone 2.5 ng / ml, IGF-1 - within normal limits). For most patients, the optimal daily dose is 0.2-0.3 mg. The maximum daily dose of 1.5 mg should not be exceeded. In patients receiving a stable dose of sandostatin, determination of the concentration of growth hormone should be carried out every 12 months. In patients with adequate control of clinical and biochemical parameters, 6-month monitoring may be required.

If after 3 months of treatment with Sandostatin there is no sufficient decrease in growth hormone levels and improvement in the clinical picture of the disease, therapy should be discontinued.

In endocrine tumors of the gastrointestinal tract and pancreas, the drug is administered subcutaneously at an initial dose of 0.05 mg 1-2 times a day. Subsequently, depending on the achieved clinical effect, the dose of the drug can be gradually increased to 0.2 mg 3 times a day. In exceptional cases, the use of the drug in higher doses may be required. Maintenance doses of the drug should be set individually. The subcutaneous route of administration is recommended, however, in cases where a rapid clinical effect is required, such as carcinoid crisis, the initial recommended dose of Sandostatin can be administered using a bolus injection after dilution of the dose with monitoring of the heart rate.

To prevent complications after pancreatic surgery, the drug is administered subcutaneously at a dose of 0.1 mg 3 times a day for the next 7 days, starting from the day of surgery (at least 1 hour before laparotomy).

For bleeding from esophageal varices, administer the drug at a dose of 25 mcg/h by continuous infusion for 5 days. Sandostatin can be diluted with 0.9% sodium chloride solution.

Use in patients with renal impairment. Renal impairment does not affect the total exposure (AUC) of octreotide administered by subcutaneous injection. Therefore, no dose adjustment of Sandostatin is required.

Use in patients with impaired liver function. In patients with cirrhosis of the liver, T ½ may increase, requiring correction of the maintenance dose.

Use in the elderly: There is no evidence of reduced tolerability or the need for dose adjustment in elderly patients treated with Sandostatin.

Contraindication

Hypersensitivity to octreotide or other components of the drug.

Side effects

The most common adverse reactions during treatment with octreotide include disorders of the gastrointestinal tract, nervous system, liver and gallbladder, metabolism and trophic disorders.

The most commonly reported adverse reactions in clinical trials of octreotide were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycemia, and constipation. Other commonly reported adverse reactions were dizziness, local pain, gallstones, thyroid dysfunction (e.g., decreased thyroid-stimulating hormone, decreased total T4, and free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia.

In rare cases, adverse reactions from the gastrointestinal tract may resemble acute intestinal obstruction - progressive abdominal distension, severe epigastric pain, abdominal tenderness and muscle tension.

A feeling of sharp pain, tingling or burning at the site of subcutaneous injection with redness and swelling rarely lasts 15 minutes. To reduce the feeling of local discomfort, the solution for injection should be at room temperature.

Although fecal fat excretion may increase, there is no indication that long-term treatment with Sandostatin can lead to the development of nutritional deficiencies due to malabsorption.

Gastrointestinal side effects can be reduced by increasing the interval between meals and administration of Sandostatin. It is recommended to administer the drug between meals or at bedtime.

In rare cases, acute pancreatitis has been reported. This phenomenon is usually observed in the first hours or days of treatment with Sandostatin and disappears after discontinuation of the drug. In addition, in patients receiving Sandostatin as a subcutaneous injection for a long time, pancreatitis due to cholelithiasis may develop.

Isolated cases of biliary colic have been reported after abrupt drug withdrawal in patients with acromegaly who have developed gallstones.

In patients with acromegaly and carcinoid syndrome, ECG changes such as QT prolongation, axis shift, early repolarization, low wave voltage, R/S transition, early R wave enlargement, and nonspecific ST-T wave changes have been observed. The relationship between these phenomena and octreotide acetate administration has not been established, since most of these patients had a history of cardiovascular disease (see Precautions).

The adverse reactions listed below in Table 1 were obtained during clinical trials of octreotide.

Adverse drug reactions are classified according to frequency: very common (≥1/10); common (≥1/100, 1/10); uncommon (≥1/1000, 1/100); rare (≥1/10,000, 1/1000); very rare (1/10,000), including isolated reports. Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse drug reactions reported in clinical trials

Post-marketing studies. The adverse reactions listed in Table 2 were reported voluntarily in spontaneous reports, and it is not always possible to reliably establish the frequency or causal relationship to drug administration.

Table 2 Adverse drug reactions described in spontaneous reports

Special instructions

Subcutaneous administration. Patients who self-administer the drug via subcutaneous injection should receive precise instructions from their doctor or nurse.

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

Ampoules should be opened only before administration, and any remaining drug should be discarded.

In / in infusion. The diluted solution remains physically and chemically stable for at least 24 hours at a temperature not exceeding 25 °C.

General: Since growth hormone-secreting pituitary tumors can occasionally enlarge and cause serious complications (e.g., visual field defects), close monitoring of the patient is essential. If signs of tumor enlargement appear, alternative treatments should be considered.

The therapeutic benefit of lowering growth hormone levels and normalizing IGF-1 concentrations in women with acromegaly may potentially restore fertility. Women of childbearing potential should be advised to use adequate contraception during treatment with octreotide (see Use in Pregnancy and Lactation).

In patients receiving long-term therapy with octreotide, thyroid function (TSH and thyroid hormones) should be monitored. During therapy with octreotide, thyroid function should be monitored.