Octreotide - instructions for use, dose, side effects, contraindications

Octreotide is a synthetic analogue of somatostatin, which is a derivative of the natural hormone somatostatin and possesses similar pharmacological effects, but a much longer duration of action. Octreotide suppresses the secretion of growth hormone (GH), both pathologically elevated, and caused by arginine, exercise and insulin hypoglycemia. The drug also inhibits the secretion of insulin, glucagon, gastrin, serotonin, both pathologically elevated and caused by food intake; also inhibits the secretion of insulin and glucagon, stimulated by arginine. Octreotide suppresses the secretion of thyrotropin, caused by thyroidiberin.

In contrast to somatostatin, octreotide suppresses the secretion of GH more than insulin secretion, and its administration is not accompanied by subsequent hypersecretion of hormones (eg, GH in patients with acromegaly).

In patients with acromegaly octreotide reduces the concentration of GH and insulin-like growth factor (IGF-1) in blood plasma. Reducing the concentration of GH by 50% or more is observed in 90% of patients, while the value of the concentration of GH at least 5 ng / ml is achieved in about half of the patients.In most patients with acromegaly octreotide reduces the severity of headache, swelling of soft tissues, hyperhidrosis, joint pain and paresthesias. In patients with large adenomas of the pituitary gland, treatment with octreotide can lead to some reduction in tumor size.

With the secreting tumors of the gastroenteropancreatic endocrine system in cases of insufficient effectiveness of the therapy (surgical intervention, embolization of the hepatic artery, chemotherapy, including streptozotocin and fluorouracil), the administration of octreotide may lead to an improvement in the course of the disease. Thus, with carcinoid tumors, the use of octreotide can lead to a decrease in the intensity of the sensation of "tides" of blood to the face, diarrhea, which in many cases is accompanied by a decrease in serotonin concentration in the plasma and excretion of 5-hydroxyindoleacetic acid by the kidneys. In tumors characterized by hyperproduction of the vasoactive intestinal peptide (WIPO), the use of octreotide in most patients leads to a reduction in severe secretory diarrhea, and, accordingly, to an improvement in the quality of life of the patient.At the same time, there is a decrease in associated electrolyte imbalance, for example, hypokalemia, which allows to cancel enteral and parenteral administration of fluid and electrolytes. Some patients slow or stop the progression of the tumor, there is a decrease in its size, as well as the size of metastases in the liver.

Clinical improvement is usually accompanied by a decrease in the concentration of vasoactive intestinal peptide (VIP) in the plasma or its normalization. With glucagonomes, the use of octreotide leads to a decrease in migrating 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 decrease in diarrhea, which is accompanied by an increase in body weight. Although the decrease in glucagon concentration in blood plasma under the influence of octreotide is transient, the clinical improvement remains stable throughout the period of application of the drug.In patients with gastrinomas / Zollinger-Ellison syndrome with octreotide in the form of monotherapy or in combination with proton pump inhibitors or blockers H₂-gistaminovyh receptors may reduce hypersecretion of hydrochloric acid in the stomach, a decrease in the concentration of gastrin in the blood plasma, as well as a decrease in the severity of diarrhea and hot flashes. In patients with insulinomas octreotide reduces the level of immunoreactive insulin in the blood (this effect can be short-term - about 2 hours). In patients with operable tumors octreotide can provide recovery 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 insulin levels in the blood.

In patients with rare tumors, hyper-producing growth hormone releasing factor (somatoliberinomas), octreotide reduces the severity of symptoms of acromegaly. This is due to the suppression of the secretion of the releasing factor of growth hormone and the growth hormone itself. In the future, the pituitary gland hypertrophy may decrease.

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, sclerosing therapy) leads to more effective stopping of bleeding and early rebleeding, reducing the volume of transfusions and improving the 5-day survival. It is believed that the mechanism of action of octreotide is associated with a decrease in organ blood flow by suppressing such vasoactive hormones as VIP and glucagon.

Pharmacokinetics:

Suction

After subcutaneous administration (sc) octreotide quickly and completely absorbed. The maximum concentration of octreotide in plasma is reached within 30 minutes.

Distribution

Communication with plasma proteins is 65%. The binding of octreotide to the formed elements of the blood is extremely insignificant. The volume of distribution is 0.27 l / kg.

Excretion

Half-life (T_1/2) after SC administration of octreotide is 100 minutes. After intravenous (iv) administration octreotide removal is carried out in 2 phases, with T_1/2 - 10 and 90 minutes, respectively. Most of the octreotide is excreted through the intestine, about 32% - in an unchanged form by the kidneys.The total clearance is 160 ml / min.

Indications:

Acromegaly - to control the main manifestations of the disease and reduce the level GH and IGF-1 in plasma in those cases when there is no sufficient effect from surgical treatment or radiation therapy. Octreotide It 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 between the radiotherapy courses until its effect is fully developed.

Secreting endocrine tumors of the gastrointestinal tract and pancreas - to control the symptoms:

- carcinoid tumors with carcinoid syndrome;

- VIPoms;

- glucagonomes;

- gastrinomas / Zollinger-Ellison syndrome - usually in combination with proton pump inhibitors and histamine H blockers₂-receptors; insulinoma (for the control of hypoglycemia in the preoperative period, as well as for maintenance therapy);

- somatoliberynoma (tumors characterized by hyperproduction of growth hormone releasing factor).

The drug is not an antitumor drug and its use can not lead to the cure of this category of patients.

Stop bleeding and prevent bleeding recurrence from varicosity enlarged veins of the esophagus and stomach in patients with cirrhosis of the liver. Octreotide are used in combination with specific therapeutic measures, for example, endoscopic sclerotherapy.

Contraindications:

- Hypersensitivity to octreotide or other components of the drug;

- children's age till 18 years.

Carefully:

- Chololithiasis (cholelithiasis);

- diabetes.

Pregnancy and lactation:

The experience with octreotide in pregnant women is limited. A drug Octreotide Use in pregnancy only if the intended benefit to the mother exceeds the potential risk to the fetus.

It is not known whether the drug enters the breast milk, so when using the drug during lactation, breastfeeding should be abandoned.

Dosing and Administration:

Subcutaneously, intravenously drip.

With acromegaly - subcutaneously, in a dose of 300 μg at intervals of 8 or 12 hours. This dose is applied in case of ineffectiveness of initial therapy (drug Octreotide, solution for intravenous and subcutaneous administration, 50-100 μg at intervals of 8 or 12 hours).The ineffectiveness of initial therapy is assessed based on monthly determinations of the concentration of GH in the blood (target concentration: GH <2.5 ng / ml, PFR-1 within normal values), analysis of clinical symptoms and drug tolerability. In the case of a dose inefficiency of 300 μg, it is recommended that the dose be selected based on the above criteria. Do not exceed the maximum dose of 1500 mcg per day.

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

With tumors of the gastroenteropancreatic endocrine system - subcutaneously, in a dose of 300 mcg 1-2 times / day. This dose is applied in case of ineffectiveness of initial therapy (drug Octreotide, a solution for intravenous and subcutaneous administration, 50 μg 1-2 times a day with a gradual increase to 100-200 μg 3 times a day). The ineffectiveness of initial therapy is assessed based on the achieved clinical effect,influence on the concentration of hormones produced by the tumor (in the case of carcinoid tumors - the effect on the release of 5-hydroxyindoleacetic acid by the kidneys) and tolerability. In exceptional cases, a dose of more than 600 μg / day may be administered to a patient, the dose of the drug can be gradually increased to 300-600 μg 3 times / day. Supportive doses of the drug should be selected individually. In carcinoid tumors, if treatment with octreotide at the maximum tolerated dose for 1 week is not effective, treatment should not continue.

When bleeding from varicose veins of the esophagus and stomach - intravenously dropwise at a rate of 25 μg / h for 5 days.

Use in selected patient groups

At present, there is no evidence to suggest that the tolerability of octreotide has been reduced in elderly people and that a change in the dosing regimen is required.

It is recommended to correct the maintenance dose in patients with impaired liver function.

In patients with impaired renal function, correction of the octreotide dosage regimen is not required.

The experience with octreotide in children is limited.

Terms of use

Subcutaneous administration

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

Before the introduction, the solution should be warmed to room temperature - this helps to reduce the unpleasant sensations at the injection site. Do not administer the drug in the same place with short periods of time. Ampoules should be opened immediately before the administration of the drug; an unused amount of solution is discarded.

Intravenous drip introduction

If you need intravenous drip octreotide, the contents of one ampoule containing 600 μg of active substance should be diluted in 60 ml of 0.9% sodium chloride solution. Octreotide at a temperature below 25 ° C for 24 hours retains physical and chemical stability in a sterile 0.9% sodium chloride solution or 5% dextrose solution in water. Nevertheless, since octreotide can affect the exchange of glucose, preferably use 0.9% solution of sodium chloride. Before intravenous administration, the ampoule should be carefully examined for changes in the color of the solution 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. Before injection, heat the solution to room temperature. The total time between dilution, storage in the refrigerator and the end of the administration of the solution should not exceed 24 hours.

Side effects:

The main undesirable effects observed with octreotide were side effects from the digestive, nervous, hepatobiliary system, as well as metabolic disorders and malnutrition.

In clinical studies, diarrhea, abdominal pain, nausea, bloating, headache, gallstones, hyperglycaemia and constipation were most frequently observed with prescribing the drug. Dizziness, pain of different localization, violation of colloidal bile stability (formation of cholesterol microcrystals), thyroid dysfunction (decrease in thyroid-stimulating hormone levels, total and free thyroxin), mild consistency of the stool, decreased glucose tolerance, vomiting, asthenia and hypoglycemia were also frequently observed.

When using the drug in rare cases, there may be phenomena reminiscent of acute intestinal obstruction: progressive bloating, severe pain in the epigastric region, abdominal wall tension, muscle "defense."

Although the release of fat with feces may increase, there is no evidence to date that prolonged treatment with octreotide can lead to malnutrition due to malabsorption. It was reported that very rare cases of acute pancreatitis, which developed in the first hours or days of octreotide application and disappeared after drug withdrawal. In addition, with long-term octreotide use, cases of pancreatitis associated with cholelithiasis were noted.

According to the ECG study on the background of the drug in patients with acromegaly and carcinoid syndrome: there was an extension of the interval QT, deviation of the electrical axis of the heart, early repolarization, low-voltage ECG type, displacement of the transition zone, early tooth P and nonspecific segment changes ST and T wave. Since there are heart diseases in this category of patients, a causal relationship between the use of octreotide and the development of these undesirable phenomena has not been established.

The following criteria were used to determine the frequency of unwanted reactions found during clinical trials: very often (≥ 1/10); often (≥ 1/100, <1/10); sometimes (≥ 1/1000, <1/100); rarely (≥1/10000, <1/1000); very rarely (<1/10000), including individual messages.

From the digestive system: very often - diarrhea, abdominal pain, nausea, constipation, bloating; often - dyspeptic abnormalities, vomiting, feeling of filling / heaviness of the abdomen, steatorrhoea, mild consistency of the stool, discoloration of the stool, anorexia.

From the nervous system: very often - headache; often - dizziness.

From the endocrine system: very often hyperglycemia; often - hypothyroidism / thyroid dysfunction (decrease in thyroid-stimulating hormone levels, total and free thyroxin); hypoglycemia, impaired glucose tolerance.

From the hepatobiliary system: very often - cholelithiasis, i.e. formation of stones in the gallbladder; often - cholecystitis, violation of colloidal stability bile (formation of microcrystals of cholesterol), hyperbilirubinemia, increased activity of hepatic transaminases.

Dermatological reactions: often - itching, rash, hair loss.

From the respiratory system: often - shortness of breath.

From the side of the cardiovascular system: often bradycardia; sometimes - tachycardia.

General disorders and reactions at the site of administration: very often - pain at the injection site; sometimes - dehydration.

On the background of therapy with octreotide, the following undesirable phenomena were noted in clinical practice, 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: hives.

From the hepatobiliary system: acute pancreatitis, acute hepatitis without the phenomena of cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, increase in the level of alkaline phosphatase, gamma-glutamyltransferase.

From the side of the cardiovascular system: arrhythmias.

Overdose:

Individual cases of octreotide overdose in children and adults have been reported in clinical practice. At random application of octreotide in adults at a dose of 2400-6000 μg / day, administered intravenously drip (infusion rate 100-250 μg / hour) or subcutaneously (1500 μg 3 times a day), there was observed: the development of arrhythmias, lowering blood pressure,sudden cardiac arrest, hypoxia of the brain, pancreatitis, fatty liver degeneration, diarrhea, weakness, inhibition, weight loss, hepatomegaly and lactic acidosis.

With occasional use of octreotide in children at a dose of 50-3000 μg / day, administered intravenously drip (infusion rate 2.1-500 μg / hr) or subcutaneously (50-100 μg), only mild hyperglycemia was noted.

When subcutaneous administration of octreotide at a dose of 3000-30000 μg / day (divided into several administrations) in patients with tumors, no new undesirable phenomena (with the exception of those indicated in the "Side effect" section) were identified.

Interaction:

Pharmacokinetic

Reduces the absorption of cyclosporine, slows the absorption of cimetidine. It is necessary to correct the dosage regimen of concomitantly used diuretics, beta-blockers, blockers of "slow" calcium channels, oral hypoglycemic drugs, glucagon.

The combined use of octreotide and bromocriptine increases the bioavailability of bromocriptine.

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

Special instructions:

For tumors of the pituitary gland secreting GH, careful monitoring of patients receiving octreotide, since it is possible to increase the size of tumors with the development of such a serious complication, as narrowing of the fields of vision. In these cases, consideration should be given to the need for other treatments.

Since reducing the level of growth hormone and normalizing the level of insulin-like factor-1 on the background of therapy with octreotide can lead to the restoration of fertility in women with acromegaly, when using the drug of a patient of childbearing age, reliable methods of contraception should be used.

With the appointment of octreotide for a long period of time, it is necessary to monitor the function of the thyroid gland.

In the case of bradycardia on the background of octreotide, if necessary, it is possible to reduce the dose of beta adrenoblockers,calcium channel blockers or drugs that affect the water-electrolyte balance.

In some patients octreotide can change the absorption of fats in the intestine.

Against the background of octreotide, there was a decrease in the content of cobalamin (vitamin B₁₂) and deviation from the norm of the indices of the cobalamin absorption test (Schilling test).

When octreotide is used in patients with vitamin B deficiency₁₂ in the anamnesis it is recommended to control the content of cobalamin in the body.

Recommendations for managing patients during drug treatment Octreotide regarding the formation of gallstones

- Before the appointment of octreotide, patients should undergo an initial ultrasound examination of the gallbladder.

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

- If gallbladder stones are found even before the start of treatment, it is necessary to evaluate the potential benefits of octreotide therapy compared to the possible risk associated with their presence. There is no data on any negative effect of octreotide on the course or prognosis of an already existing cholelithiasis.

Management of patients whose gallstones are formed during the treatment with Octreotide

- Asymptomatic stones of the gallbladder.

The use of octreotide can be discontinued or continued - according to the benefit / risk ratio estimate. In any case, there is no need to do anything other than to continue monitoring, if necessary, making it more frequent.

- Stones of the gallbladder with clinical symptoms.

The use of octreotide can be discontinued or continued - according to the benefit / risk ratio estimate. In any case, the patient should be treated in the same way as in other cases of cholelithiasis with clinical manifestations. 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 in the same dose) under ultrasound control until the stones disappear completely.

In the treatment of endocrine tumors of the gastrointestinal tract and pancreas with octreotide, in rare cases, sudden recurrence of symptoms of the disease may occur.

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

Since after the bleeding from the varicose veins of the esophagus and stomach increased the risk of developing type 1 diabetes, and in patients with diabetes, there is also a possible change in the need for insulin, in these cases, a systematic control of the concentration of glucose in the blood.

It is necessary to correct the dosage regimen of concomitantly used diuretics, beta-blockers, slow calcium channel blockers, insulin, oral hypoglycemic agents, glucagon.

Effect on the ability to drive transp. cf. and fur:

Some of the side effects of octreotide can adversely affect the ability to drive vehicles and other mechanisms that require increased concentration and speed of the speed of psychomotor reactions. In this regard, it is recommended that when these symptoms occur, use caution when operating vehicles or mechanisms that require increased concentration.

Form release / dosage:

Solution for intravenous and subcutaneous administration, 300, 600 μg / ml.

Packaging:

1 ml per ampoule of colorless glass with a color marking in the form of two green strips or in ampoules of dark glass, having a ring of tension for opening or ampoule with a break point.

For 1 ampoule with a dosage of 300 or 600 μg / ml in a contiguous cell pack of a polyvinyl chloride film.

For 2 ampoules with a dosage of 300 or 600 μg / ml in a contiguous cell pack of a polyvinyl chloride film.

For 5 ampoules with a dosage of 300 or 600 μg / ml in a contiguous cell pack of a polyvinyl chloride film.

1 contour cell package containing 1, 2, 5 ampoules, or 2 contour cells containing 5 ampoules, together with the instruction for use, is placed in a pack of cardboard.

Storage conditions:

In a dry, dark place at a temperature of 8 to 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002453

Date of registration:06.05.2014 / 18.11.2016

Expiration Date:06.05.2019

The owner of the registration certificate:FARM-SYNTHESIS, CJSC FARM-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

Company DEKO, LLC Russia

Representation: & nbspFARM-SYNTHESIS CJSC FARM-SYNTHESIS CJSC Russia

Information update date: & nbsp29.05.2017

Illustrated instructions

Instructions

Octreotide (Octreotide)