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

Octreotide is a synthetic octapeptide, which is a derivative of the natural hormone somatostatin and possesses similar pharmacological properties, but a much longer duration of action. Octreotide suppresses the secretion of growth hormone (GH), as well as peptides and serotonin produced by secretory endocrine tumors of the gastrointestinal tract (GIT) and pancreas. In healthy volunteers octreotide, like somatostatin, suppressed the secretion of GH caused by arginine, exercise and insulin hypoglycemia. Octreotide inhibits the secretion of insulin, glucagon, gastrin, and other peptides secreting endocrine tumors of the gastrointestinal tract (GIT) and pancreas induced food intake, also suppresses the secretion of insulin and glucagon stimulated with arginine. Octreotide also suppresses the secretion of thyrotropin, caused by thyroidiberin.

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

The use of octreotide before and after surgery on the pancreas reduced the frequency of typical postoperative complications (for example, pancreatic fistula formation, abscesses and development of sepsis and postoperative acute pancreatitis).

Acromegaly

In patients with acromegaly octreotide reduces the concentration of GH and insulin-like growth factor (IGF-1) in blood plasma. In most patients octreotide reduced the severity of clinical symptoms of the disease - headache, hyperhidrosis, paresthesia, fatigue, joint pain and carpal tunnel syndrome. In individual patients with pituitary adenoma, the use of octreotide reduced the size of the tumor.

Secreting endocrine tumors of the gastrointestinal tract (GIT) and pancreas

In patients with secreting endocrine tumors of the gastrointestinal tract (GIT) and pancreas in cases of insufficient effectiveness of the therapy (surgical intervention, embolization of the hepatic artery, chemotherapy, including streptozotocin and fluorouracil), the use of octreotide can lead to an improvement in the coursedisease. The effect of octreotide on tumor size, progression and metastasis has not been clearly demonstrated.

Carcinoid tumors

The use of octreotide can lead to a decrease in the severity of the symptoms of the disease, especially the "tides" of blood to the face and diarrhea. In many cases, clinical improvement is accompanied by a decrease in serotonin concentration in plasma and excretion of 5-hydroxyindoleacetic acid by the kidneys.

Tumors characterized by hyperproduction of the vasoactive intestinal peptide (VIPoma)

The use of octreotide in WIPO in most cases leads to a reduction in severe secretory diarrhea, typical for this disease, which in turn leads to an improvement in the patient's quality of life. At the same time, there is a decrease associated abnormalities of electrolyte balance, for example, hypokalemia, which allows to cancel enteral and parenteral administration of liquid electrolytes. Some patients slowed or stopped the progression of the tumor,there was 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 plasma to normal values.

Glucagon

The use of octreotide in most cases leads to a significant reduction in migrating erythema, which is characteristic of this disease. Octreotide has no significant effect on the severity of hyperglycemia in diabetes mellitus, while the need for insulin and oral hypoglycemic drugs usually remains unchanged. Octreotide significantly reduces 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 when using octreotide in the form of monotherapy or in combination with proton pump inhibitors or H blockers₂-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 the "tides" of blood to the face.

Patients from insulinomas Octreotide reduces the concentration 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 or malignant tumors, the control of glycemia can be improved without a simultaneous prolonged decrease in insulin concentration in the blood.

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

Preventive maintenance of complications after operations on a pancreas

Studies have shown that the use of octreotide during or after surgery on the pancreas reduces the incidence of a typical postoperative complication, such as fistula formation. The frequency of other postoperative complications, such as the development of an abscess that increases the risk of sepsis and acute pancreatitis, is reduced in lesser degree. The study involved patients with the planned pancreas resection and / or pancreatojunostomy for pancreatic tumors, periampular carcinoma, or chronic pancreatitis.

Pharmacokinetics:

Suction

After subcutaneous administration octreotide quickly and completely absorbed.

The maximum concentration of octreotide (C_mOh) in plasma is achieved within 30 minutes.

Distribution

Binding to plasma proteins is 65%. Octreotide practical does not bind to the shaped elements of the blood. The volume of distribution is 0.27 l / kg.

Excretion

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

In patients with impaired renal function, subcutaneous administration of octreotide does not affect the total exposure - the area of the "concentration-time" curve (AUC). Octreotide excretion may decrease in patients with cirrhosis, but does not change in patients with steatohepatitis.

Indications:

- Acromegaly - symptomatic treatment and decrease in the concentration of GH and IGF-1 in blood plasma in those cases when there is insufficient effect from surgery or radiation therapy.

Octreotide Kabi is also indicated for the treatment of patients who have refused surgery or who have contraindications to it, as well as for short-term treatment at the initial stage of radiotherapy before the development of its full effect.

- 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 blockers H₂-receptors;
insulinomas (for the control of hypoglycemia in the preoperative period, and for maintenance therapy);
somatoliberalinoma (a tumor characterized by hyperproduction of the GH rylening factor).

Octreotide Kabi is not an antitumor drug and its use does not allow to cure this category of patients.

- Prevention of complications after operations on the pancreas.

Contraindications:

- Hypersensitivity to octreotide or other components of the drug;

- Children's age under 18 years (lack of data on safety and effectiveness).

Carefully:

The drug Octreotide Cubi should be administered with caution in cholelithiasis, diabetes, pregnancy and with simultaneous use with drugs with a narrow therapeutic index, the metabolism of which is carried out with the participation of isoenzyme CYP3A4.

Pregnancy and lactation:

Pregnancy

Data on the use of octreotide in pregnant women are absent or limited. Given the suppression of GH, it can be assumed that the use of octreotide may pose a threat to the fetus. In studies in animals, there was a temporary growth retardation in the offspring, possibly due to the endocrine profile of the animals being studied, while signs of fetotoxicity, teratogenicity, or changes in reproductive function were absent. Possible risk to humans is not established. In this regard, the drug Octreotide Cubi should not be used during pregnancy,when the intended use for the mother exceeds the potential risk to the fetus. Women of reproductive age should use reliable contraceptives during therapy.

Breastfeeding period

It is not known whether the octreotide or its metabolites into breast milk, therefore, it is impossible to exclude the risk for newborns during breastfeeding. In animals, octreotide penetrates into the milk. If it is necessary to use octreotide during lactation, it is recommended to stop breastfeeding.

Dosing and Administration:

A drug Octreotide Kibi is recommended to be administered intravenously or subcutaneously.

Acromegaly

The initial dose of the drug is 50-100 μg and is administered subcutaneously at intervals 8 or 12 hours. Further the dose is selected on the basis of a monthly assessment of the concentration of GH and IFG-1 in blood plasma (target concentrations: GH <2.5 ng / ml: IFG-1 within normal limits), analysis of clinical symptoms and drug tolerability.

In most patients, the optimal daily dose is 200-300 μg. Do not exceed the maximum daily dose of 1500 μg.In patients receiving the preparation Octreotide Cabi in a stable dose, the determination of the concentration of GR in the blood plasma should be carried out every 6 months. If, 3 months after the start of therapy, there is no significant reduction in the concentration of GH in the blood plasma or an improvement in the clinical picture of the disease, therapy should be discontinued.

Secreting endocrine tumors of the gastrointestinal tract (GIT) and pancreas

The initial dose of the drug is 50 mcg and administered subcutaneously 1 or 2 times a day. In the future, depending on the clinical effect achieved, the effect on the concentration of hormones produced by the tumor (in the case of carcinoid tumors, excretion of 5-hydroxydolacetic acid by the kidneys) and drug tolerance, the dose can be gradually increased to 100-200 μg 3 times a day. In exceptional cases, higher doses are required. Supportive doses of the drug should be selected individually.

The drug Octreotide Kabi is recommended to be administered subcutaneously. However, if it is necessary to achieve a rapid effect, for example, in a carcinoid crisis, the recommended initial dose of octreotide can be diluted and administered intravenously bolus during cardiac rhythm monitoring.

If therapy with Octreotide Cabi in patients with carcinoid tumors in the maximum tolerated dose for 1 week was not effective, the drug should be discontinued.

Preventive maintenance of complications after operations on a pancreas

100 mcg subcutaneously 3 times a day for 7 days, treatment is started from the day of surgery (according to at least 1 hour before laparotomy).

Patients with impaired renal function

With subcutaneous administration, decreased renal function did not affect exposure (AUC) octreotide. Correction of the dose is not required.

Patients with impaired hepatic function

In patients with cirrhosis of the liver, the duration of T_1/2octreotide, which requires correction of the maintenance dose.

Elderly patients

In elderly patients, no deterioration was noted in the treatment with octreotide tolerability or need for dose adjustment.

Children

There are no data on the use of Octreotide Kabi.

Application rules

In use, Octreotide Kabi can be stored in its original packaging to protect it from light, at temperatures not exceeding 25 ° C, for a maximum of 2 weeks. Before use, the solution should be checked for transparency, presence of foreign particles and discoloration of the solution.

Subcutaneous administration:

Patients who self-administer subcutaneous administration of Octreotide Kabi should receive detailed instructions from a doctor or health care provider. Before administration, the solution is recommended to be kept at room temperature, since the administration of a warmed solution helps to reduce the unpleasant sensations at the injection site. Multiple injections of the drug should be avoided in the same place for a short period of time. The drug should be administered immediately after opening the vial; Unused solution residues should be disposed of. The drug Octreotide Cabi should not be diluted for subcutaneous administration.

Intravenous administration:

For intravenous administration, Octreotide Cabi should be diluted with a solution of sodium chloride 9 mg / ml in a ratio of at least 1: 1 and not more than 1: 9 by volume. Because the octreotide can affect the metabolism of glucose, the drug Octreotide Kabi is not recommended to dilute with glucose solution.

The prepared solution is chemically and physically stable for 24 hours at room temperature. To avoid microbial contamination, the prepared solution should be applied immediately after dilution.Unused solution residues should be disposed of.

Side effects:

The main adverse events (AEs) observed with octreotide were side effects from the gastrointestinal tract. nervous, hepatobiliary systems, as well as metabolic and nutritional deficiencies.

In clinical studies, diarrhea, abdominal pain, nausea, bloating, headache, cholelithiasis, hyperglycemia and constipation were most frequently observed with octreotide.

Other frequent AEs were dizziness, pain of different localization, violation of colloidal bile stability (formation of microcrystals of cholesterol), thyroid dysfunction (in particular reduction in thyroid-stimulating hormone [TSH], total and free thyroxin levels), mild stool consistency, decreased glucose tolerance, vomiting, asthenia, and hypoglycemia.

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

To reduce the risk of side effects from the gastrointestinal tract, it is recommended to avoid eating during octreotide injections. Octreotide should be administered between meals or at bedtime.

Pain or sensation of tingling or burning at the site of subcutaneous injection, accompanied by reddening and swelling and rarely persisting for more than 15 minutes. To reduce discomfort at the injection site, the solution should be warmed to room temperature before administration.

There were reported very rare cases of acute pancreatitis that developed in the first hours or days after subcutaneous application of octreotide, and disappeared after the drug was discontinued. In addition, with prolonged subcutaneous administration of octreotide, patients had cases of pancreatitis associated with cholelithiasis.

Individual cases of biliary colic were reported after abrupt discontinuation of the drug in patients with acromegaly, who had a violation of colloidal bile stability (formation of cholesterol microcrystals) or cholelithiasis.

According to the ECG study, when the drug was used in patients with acromegaly and carcinoid syndrome, 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 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 AE data has not been proved.

To determine the frequency of AH revealed in the course of clinical trials of the drug, the following criteria were used: very often (≥1 / 10); often (≥1 / 100 to <1/10); infrequently (≥1 / 1,000 to <1/100); rarely (≥1 / 10,000 to <1 / 1,000); very rarely (<1 / 10,000); It is not known (can not be established on the basis of available data).

In each group, AEs are arranged in descending order of severity.

From the endocrine system: often - hypothyroidism / thyroid dysfunction gland (decrease in thyroid-stimulating hormone concentration, decrease in total and free thyroxine).

From the side of metabolism and nutrition: very often - hyperglycemia; often - hypoglycemia, impaired glucose tolerance; infrequently - dehydration.

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

From the heart: often bradycardia; infrequently - a tachycardia.

On the part of the respiratory system, the organs of the thorax and the mediastinum: often - shortness of breath.

From the gastrointestinal tract: very often - diarrhea, abdominal pain, nausea, constipation, bloating; often - dyspeptic disorders, vomiting, feeling of filling / heaviness of the abdomen, steatorrhea, mild consistency of the stool, discoloration of the stool, anorexia; rarely - acute intestinal obstruction, epigastric pain, abdominal wall tension, muscular "defense", acute pancreatitis, pancreatitis associated with cholelithiasis.

From the liver and biliary tract: very often - cholelithiasis; often - cholecystitis, violation of the colloidal stability of bile (formation of microcrystals of cholesterol), hyperbilirubinemia.

From the skin and subcutaneous tissues: often - itching, rashes, alopecia.

General disorders and disorders at the site of administration: very often - pain at the injection site.

Laboratory and instrumental data: often - increased activity aminotransferases.

On the background of therapy with octreotide, the following AEs were observed in clinical practice, regardless of the presence of a cause-and-effect relationship with the use of the drug:

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

From the heart: arrhythmias.

From the liver and biliary tract: acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.

From the skin and subcutaneous tissues: hives.

Laboratory and instrumental data: increased activity of alkaline phosphatase, gamma-glutamyltransferase.

Overdose:

Individual cases of octreotide overdose in adults and children have been reported in clinical practice. In the case of the random use of octreotide in adults at a dose of 2,400 to 6,000 μg / day with intravenous infusion (infusion rate 100-250 μg / h) or subcutaneously (1500 μg three times a day), the following AEs were observed: arrhythmia, lowering blood pressure, sudden stop heart, hypoxia of the brain, pancreatitis, steatohepatosis, hepatitis, diarrhea, asthenia, drowsiness, weight loss, hepatomegaly and lactic acidosis.

With the occasional use of octreotide in children at a dose of 50 to 3000 μg / day with intravenous infusion (infusion rate of 2.1-500 μg / h) or subcutaneously (50-100 μg), only AH was moderately hyperglycemic.

With subcutaneous administration of octreotide in doses from 3000 to 30,000 μg / day (divided into several receptions) in patients with tumors,No new AEs (with the exception of those indicated in the "Side effect" section) have been identified.

In case of an overdose with octreotide, symptomatic treatment is performed.

Interaction:

Octreotide reduces the absorption of cyclosporine in the intestine and slows the absorption of cimetidine.

With the simultaneous use of octreotide with bromocriptine, the bioavailability of the latter increases.

There is evidence that somatostatin analogues can reduce metabolic drug clearance, which occurs with the participation of cytochrome P450 isoenzymes (may be due to GH suppression). Since such an octreotide effect can not be ruled out, care should be taken when using drugs metabolized with isoenzyme CYP3A4, and having a narrow range of therapeutic concentrations (e.g., quinidine, carbamazepine, digoxin, fenprokumone and terfenadine).

Octreotide reduces hepatic blood flow by about 30%, so you should consider the possibility of interacting with drugs whose metabolism depends on the hepatic blood flow.

It is necessary to correct the dosage regimen of concomitant diuretics, beta-blockers,blockers of "slow" calcium channels, insulin, oral hypoglycemic drugs, glucagon.

Special instructions:

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

If surgical treatment or radiation therapy is not possible, patients with tumors secreting GH may require life-long therapy with octreotide.

Since reducing the concentration of GH and normalizing the concentration of IGF-1 in blood plasma can lead to the restoration of fertility in women with acromegaly, with the use of Octreotide Kabi, patients of reproductive age should use reliable methods of contraception (see the section "Use in pregnancy and in the period of breast feeding ").

Patients receiving long-term therapy with octreotide should monitor the function of the thyroid gland.

In the case of bradycardia on the background of therapy with Octreotide Kabi, if necessary, you can reduce the dose of beta-adrenoblockers, blockers of "slow" calcium tubules or drugs that affect the water-electrolyte balance.

In the treatment of endocrine tumors of the gastrointestinal tract and pancreas with octreotide, in rare cases there is a sudden relapse of the expressed symptoms of the disease.

To reduce unwanted reactions from the gastrointestinal tract with octreotide, it is recommended to administer Octreotide Cabi between meals or at bedtime.

Metabolism of glucose

Octreotide inhibits the secretion of GH, glucagon and insulin and, accordingly, can influence glucose metabolism. There may be an increase in postprandial glycemia, and in some cases prolonged treatment may develop persistent hyperglycemia. There have been cases of developing hypoglycemia. When using Octreotide Kabi, systematic monitoring of blood glucose in patients is recommended.

Octreotide inhibits the secretion of GH and glucagon more than insulin, and the duration of its inhibitory effect on insulin secretion is shorter,therefore, in patients with insulinoma, the drug may cause an increase in the severity and duration of hypoglycemia. Patients with insulinoma receiving octreotide, should be under close supervision, especially at the beginning of therapy and when adjusting the dose. Treatment should begin in a hospital. Significant fluctuations in the concentration of glucose in the blood can be reduced by more frequent administration of smaller doses octreotide.

Octreotide can reduce the need for insulin and oral hypoglycemic drugs in patients with type 1 diabetes. In patients without diabetes mellitus and type 2 diabetes mellitus with partially preserved insulin secretion, the administration of octreotide may lead to postprandial hyperglycemia. In this regard, it is recommended to monitor the concentration of glucose in the blood and correct for hypoglycemic drugs.

Undesirable effects from the gallbladder

Octreotide suppresses gallbladder motility, bile acid secretion and bile secretion, and its use can be accompanied by cholelithiasis. The frequency of development of cholelithiasis in the application of octerotide is 15-30%.

Before the appointment of therapy with octreotide, and every 6-12 months of therapy, patients should perform ultrasound (ultrasound) of the gallbladder. The presence of gallbladder stones is usually not accompanied by clinical symptoms. When clinical symptoms appear, standard treatment is performed.

If gallbladder stones are found even before the start of treatment, it is necessary to evaluate the potential benefits of octreotide therapy in comparison with the possible risk associated with the presence of gallstones. It is necessary to take into account the consequences of abrupt withdrawal of the drug

A patient with cirrhosis of the liver may need a dose adjustment (see section "Method of administration and dose").

Food

In some patients octreotide can change the absorption of fats in the intestine. Although the release of fat with feces may increase, there is no evidence to date that prolonged use of octreotide can lead to malnutrition due to malabsorption. With prolonged use, it is recommended to control the excretion of fats with feces and, if necessary, take appropriate measures.

Against the background of the use of octreotide, in some patients there was a decrease in the content of cyanocobalamin (vitamin B₁₂) and the deviation from the norm of the indices of the cyanocobalamin absorption test (Schilling test). When octreotide is used in patients with a history of cyanocobalamin deficiency in the treatment with octreotide, it is recommended to monitor its content in the body.

When octreotide is used in patients with acromegalycan break the reproductive function.

Women of reproductive age should to use reliable means of contraception at application of a preparation.

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

Studies of the effect on the ability to drive vehicles and mechanisms have not been carried out.

Form release / dosage:

Solution for intravenous and subcutaneous administration, 50 μg / ml, 100 μg / ml.

Packaging:

1 ml of the drug in a bottle of colorless glass type I with a capacity of 2 ml, corked with rubber (halobutyl) stopper with fluorocarbon protective film and crimped with an aluminum cap with a protective plastic cover (first opening control).

For 5 bottles together with instructions for use in a pack of cardboard.

Storage conditions:

Store at a temperature of 2 to 8 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003674

Date of registration:14.06.2016

Expiration Date:14.06.2021

The owner of the registration certificate:Fresenius Kabi Deutschland GmbHFresenius Kabi Deutschland GmbH Germany

Representation: & nbspFresenius Kabi, OOOFresenius Kabi, OOORussia

Information update date: & nbsp02.06.2017

Illustrated instructions

Instructions

Octreotide Kabi (Octreotid Kabi)