Composition, form of production and packaging
Solution for iv and n / to the introduction is transparent, colorless, odorless.
1 ml
octreotide (in the form of acetate) 300 Ојg
Excipients: sodium chloride - 9 mg, water d / and - up to 1 ml.
1 ml - ampoules (1) - packings the cellular contour (1) - packs cardboard.
1 ml - ampoules (2) - packings of cellular contour (1) - packs cardboard.
1 ml - ampoules (5) - packings of cellular contour (1) - packs cardboard.
1 ml - ampoules (5) - packings the cellular contour (2) - packs cardboard.
Solution for iv and n / to the introduction is transparent, colorless, odorless.
1 ml
octreotide (in the form of acetate) 600 Ојg
Excipients: sodium chloride - 9 mg, water d / and - up to 1 ml.
1 ml - ampoules (1) - packings the cellular contour (1) - packs cardboard.
1 ml - ampoules (2) - packings of cellular contour (1) - packs cardboard.
1 ml - ampoules (5) - packings of cellular contour (1) - packs cardboard.
1 ml - ampoules (5) - packings the cellular contour (2) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
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.
Unlike somatostatin, octreotide suppresses GH secretion 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.
When 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 appointment of octreotide can 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 blood flushes to the face, diarrhea, which in many cases is accompanied by a decrease in serotonin concentration in 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 H2-histamine receptor blockers, hypersecretion of hydrochloric acid in the stomach, a decrease in the concentration of gastrin in the blood plasma, and a decrease in the severity of diarrhea and tides. 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 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 insulin levels in the blood.
In patients with rare tumors, hyper-growth hormone releasing factor (somatoliberinomas), octreotide reduces the severity of the 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-dilated esophagus and stomach veins in patients with cirrhosis of the liver, the use of octreotide in combination with specific treatment (eg, sclerosing therapy) leads to more effective stopping of bleeding and early rebleeding, a decrease in transfusion volume, and an improvement in 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 sc administration octreotide is quickly and completely absorbed. C max octreotide in plasma is achieved within 30 min.
Distribution
Communication with plasma proteins is 65%. The binding of octreotide to the formed elements of the blood is very insignificant. V d is 0.27 l / kg.
Excretion
T 1/2 after SC administration of octreotide is 100 minutes. After intravenous administration octreotide removal is carried out in 2 phases, with T 1/2 - 10 and 90 min, 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 of GH and IGF-1 in plasma in those cases when 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 who have contraindications to it, as well as for short-term treatment 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;
- Glucagon;
- gastrinomas / Zollinger-Ellison syndrome - usually in combination with proton pump inhibitors and histamine H2-blockers;
- insulinoma (for the control of hypoglycemia in the preoperative period, as well as for maintenance therapy);
- somatoliberynomas (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.
Stopping bleeding and preventing recurrence of bleeding from varicose-esophageal veins of the esophagus and stomach in patients with cirrhosis of the liver.Octreotide is used in combination with specific therapeutic measures, for example, endoscopic sclerosing therapy.
DOSING MODE
Subcutaneously, intravenously drip.
In acromegaly , sc, at a dose of 300 Ојg at intervals of 8 or 12 hours. This dose is applied in case of ineffectiveness of initial therapy (Octreotide, IV solution and SC, 50-100 Ојg 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, IGF-1 within normal values), analysis of clinical symptoms and drug tolerability. In the case of a dose inefficiency of 300 Ојg, it is recommended that the dose be selected based on the above criteria. Do not exceed the maximum dose of 1500 Ојg / day.
In patients receiving octreotide in a stable dose, the determination of the GH concentration should be performed 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: SC, at a dose of 300 Ојg 1-2 times / day. This dose is applied in case of ineffectiveness of initial therapy (Octreotide preparation, IV solution and SC administration, 50 Ојg 1-2 times / day with gradual increase up to 100-200 Ојg 3 times / day). The ineffectiveness of initial therapy is assessed based on the clinical effect achieved, the effect 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 exceeding 600 Ојg / day can be administered to a patient, the dose of the drug can be gradually increased to 300-600 Ојg 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-dilated veins of the esophagus and stomach: intravenously, drip at a rate of 25 mcg / 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 independently carry out the SC administration of octreotide 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 necessary in / in the drip octreotide, the contents of one ampoule containing 600 Ојg of active substance should be diluted in 60 ml of 0.9% sodium chloride solution. Octreotide at a temperature below 25 В° C for 24 hours retains physical and chemical stability in a sterile 0.9% solution of sodium chloride or 5% dextrose in water. However, since octreotide can affect glucose metabolism, it is preferable to use 0.9% sodium chloride solution. Before / in the introduction of 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 В° 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 EFFECT
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, hyperglycemia and constipation were most frequently observed with prescription of the drug. Also, 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), soft stool consistency, decreased glucose tolerance, vomiting, asthenia and hypoglycemia were often noted.
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 protection.
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 prolonged use of octreotide, the incidence of pancreatitis associated with cholelithiasis was noted.
According to the ECG data, studies with the use of the drug in patients with acromegaly and carcinoid syndrome showed prolongation of the QT interval, deviation of the electrical axis of the heart, early repolarization, low-voltage ECG type, displacement of the transition zone, early tooth P and nonspecific changes in segment ST and tooth T. 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.
To determine the frequency of unwanted reactions revealed during clinical trials of the drug, the following criteria were used: 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 bile stability (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 cardiovascular system: often - bradycardia; sometimes - tachycardia.
General disorders and reactions at the injection site: 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:
On the part of 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 alkaline phosphatase, gamma-glutamyltransferase.
From the cardiovascular system: arrhythmias.
CONTRAINDICATIONS
- hypersensitivity to octreotide or other components of the drug;
- Children under 18 years.
With caution: cholelithiasis (cholelithiasis); diabetes
PREGNANCY AND LACTATION
The experience with octreotide in pregnant women is limited. Octreotide should be used during 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.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with impaired renal function, correction of the octreotide dosage regimen is not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
It is recommended to correct the maintenance dose in patients with impaired liver function .
APPLICATION FOR CHILDREN
The experience with octreotide in children is limited.
APPLICATION IN ELDERLY PATIENTS
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.
SPECIAL INSTRUCTIONS
With pituitary tumors secreting GH, careful monitoring of patients receiving octreotide is necessary, since it is possible to increase the size of tumors with the development of such a serious complication as narrowing of the visual fields. In these cases, consideration should be given to the need for other treatments.
Since the reduction of growth hormone and normalization of IGF-1 level to octreotide therapy may lead to restoration to fertility in women with acromegaly patient when applying the preparation of childbearing age must use a reliable means of contraception.
When assigning octreotide over an extended period of time necessary to monitor thyroid function.
In the case of bradycardia during treatment with octreotide, if necessary, may reduce the dose of beta-blockers, calcium channel blockers or drugs that affect the water-electrolyte balance.
In some patients, Octreotide may alter absorption of fats in the intestine.
Against the background of octreotide noted reduction of cobalamin (vitamin B 12 ) and abnormal indicators of cobalamin absorption test (Schilling test).
In the application of octreotide in patients with deficiency of vitamin B 12 in anamnesis it is recommended to control the content of cobalamin in the body.
Prior to the appointment of octreotide patients should undergo initial ultrasound examination of the gallbladder.
During treatment with Octreotide should be repeated ultrasound examination of the gallbladder, preferably at intervals of 6-12 months.
If gallstones are found before the start of the treatment, it is necessary to evaluate the potential benefits of therapy with octreotide compared with the potential risks associated with their presence. Information about any negative effect of octreotide on the course or prognosis existing cholelithiasis not.
Asymptomatic gallstones . The use of octreotide can stop or continue - in line with the assessment of benefit / risk ratio. In any case, there is no need to do anything except to continue monitoring, making it more frequently if necessary.
Gallstones symptomatic.The use of octreotide can stop or continue - in line with the assessment of benefit / risk ratio. In any case, the patient should be treated in the same way as in other cases of gallstone disease with clinical manifestations. Drug treatment includes the use of combinations of bile acids preparations (e.g., chenodeoxycholic acid at a dose of 7.5 mg / kg per day in combination with ursodeoxycholic acid at the same dose) under ultrasound guidance - until complete disappearance of stones.
In the treatment of gastrointestinal and pancreatic endocrine tumors octreotide in rare cases may occur sudden recurrence of disease symptoms.
Patients with insulinomas during treatment with octreotide can be marked increase in the severity and duration of hypoglycemia (this is due to more pronounced overwhelming effect on GH secretion and glucagon than insulin secretion, as well as the shorter duration of inhibition of insulin secretion). It should ensure thorough regular monitoring of these patients at the beginning of treatment with octreotide, and at each change of dosage. Substantial fluctuations in blood glucose concentration can try to reduce by more frequent dosing of octreotide in smaller doses. In patients with diabetes type 1 diabetes, octreotide can reduce the need for insulin. In patients without diabetes and type 2 diabetes with partly intact insulin secretion administering octreotide may result in postprandial hyperglycemia.In the application of octreotide in patients with diabetes is recommended to control blood glucose concentration and antidiabetic therapy.
Because after bleeding from varicose veins of the esophagus and stomach increased risk of developing type 1 diabetes mellitus, and in patients suffering from diabetes are also possible changes in insulin requirements in these cases, the regular control of blood glucose concentration.
Requires correction dosing regimen simultaneously used diuretics, beta-blockers, blockers "slow" calcium channels, insulin, oral hypoglycemic agents, glucagon.
Impact on the ability to drive vehicles and manage mechanisms
Some side effects of octreotide may adversely affect the ability to drive vehicles and other machines that require high concentration and speed of psychomotor speed reactions. In this context it recommended for these symptoms to be careful when driving or mechanisms that require high concentration.
OVERDOSE
It reported some cases of overdose of octreotide in children and adults in clinical practice. Accidental application of octreotide in adults at a dose of 2400-6000 mg / day, administered in / drip (infusion rate
of 100-250 g / h) or s / (1500 mg 3 times / day) were observed: the development of arrhythmias, blood pressure reduction , sudden cardiac arrest, brain hypoxia, pancreatitis, fatty liver, diarrhea, weakness, lethargy, weight loss, hepatomegaly, and lactate acidosis.
Accidental application of octreotide in children at a dose of 50-3000 mg / day, administered in / drip (infusion rate of 2.1-500 g / h), or n / k (50-100 mg), there was only a moderate degree of hyperglycemia.
For n / to the introduction of octreotide dose 3000-30000 mg / day (divided into more administrations) in patients with tumors of any new adverse events (except as noted in "Side effect") have been identified.
DRUG INTERACTION
Pharmacokinetic interaction
reduces absorption of cyclosporine, slows the absorption of cimetidine. Requires correction dosing regimen simultaneously used diuretics, beta-blockers, blockers "slow" calcium channels, oral hypoglycemic drugs, glucagon.
Combined application of octreotide and bromocriptine increases the bioavailability of bromocriptine.
Decreases metabolism substances metabolized involving cytochrome P450 enzymes (may be due to the suppression of GH). Since we can not exclude similar effects octreotide, caution should be exercised when administering the drug metabolized by cytochrome P450 system and having a narrow range of therapeutic concentrations (e.g., quinidine, terfenadine).
TERMS OF RELEASE FROM PHARMACY
The preparation is available on medical prescription.
TERMS AND CONDITIONS OF STORAGE
Harney drug should be dry, protected from light, out of reach of children at a temperature of 8 to 25 В° C.
Shelf life - 5 years. Do not use after expiry date.
