Octreotide-MB solution for injection 0.1 mg/ml ampoule 1 ml No. 5

Instructions for use Octreotide-MB solution for injection 0.1 mg/ml ampoule 1 ml No. 5

Composition

active ingredient: octreotide;

1 ml of solution contains octreotide acetate equivalent to octreotide 0.05 mg or 0.1 mg or 0.5 mg;

excipients: mannitol (E 421), lactic acid, sodium bicarbonate, water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: clear colorless liquid.

Pharmacotherapeutic group

Hormone preparations for systemic use. Pituitary and hypothalamic hormones. Hypothalamic hormones. Somatostatin and analogues. Octreotide.

ATX code H01C B02.

Pharmacological properties

Pharmacodynamics.

Octreotide is a synthetic octapeptide that is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a much longer duration of action. The drug inhibits pathologically increased secretion of growth hormone (GH), 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 inhibition.

In healthy individuals, Octreotide-MB inhibits:

growth hormone secretion induced by arginine, exercise, and insulin hypoglycemia;

secretion of insulin, glucagon, gastrin and other peptides of the gastroenteropancreatic endocrine system, which is caused by food intake, as well as secretion of insulin and glucagon, which is stimulated by arginine;

thyrotropin secretion induced by thyrotropin-releasing hormone.

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

In patients with acromegaly, Octreotide-MB reduces the concentration of GH and insulin-like growth factor 1 (IGF-1) in the blood plasma. In 90% of patients, GH suppression by 50% or more is observed; a decrease in plasma GH levels of less than 5 ng/ml is achieved in approximately half of the patients. In most patients with acromegaly, Octreotide-MB 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 secreting GH, treatment with Octreotide-MB may lead to some reduction in tumor size.

In patients with functional endocrine tumors of the gastrointestinal tract and pancreas, Octreotide-MB, due to its various endocrine effects, affects a number of clinical signs of the disease. Clinical and symptomatic improvement is observed in patients who still have symptoms related to the tumors despite previous treatment, which may include surgery, hepatic artery embolization and various chemotherapy, such as the use of streptozotocin and 5-fluorouracil.

The effects of Octreotide-MB on various types of tumors are described below.

In carcinoid tumors, the use of Octreotide-MB may lead to a decrease in the severity of symptoms such as flushing and diarrhea, which in many cases is accompanied by a decrease in plasma serotonin concentration and urinary excretion of 5-hydroxyindoleacetic acid.

In tumors characterized by hyperproduction of vasoactive intestinal peptide (VIP), the use of Octreotide-MB leads to a decrease in the severe secretory diarrhea characteristic of this condition in most patients, which, in turn, improves the patient's quality of life. At the same time, concomitant electrolyte imbalances, such as hypokalemia, are reduced, which allows for the abolition of enteral and parenteral administration of fluids and electrolytes. As shown by computed tomography, in some patients, tumor progression slows down or stops and even reduces its size, especially liver metastases. Clinical improvement is usually accompanied by a decrease (even to normal values) in the concentration of VIP in the blood plasma.

In glucagonomas, the use of the drug in most cases leads to a noticeable reduction in necrotizing migratory rashes, which are characteristic of this condition. Octreotide-MB does not show any significant effect on 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 suffering from diarrhea, the drug helps to reduce it, which is accompanied by an increase in body weight. When using Octreotide-MB, a rapid decrease in the concentration of glucagon in the blood plasma is often noted, however, with prolonged treatment this effect is not maintained. At the same time, symptomatic improvement remains stable for a long time.

In patients with insulinomas, Octreotide-MB reduces the level of immunoreactive insulin in the blood. This effect, however, may be short-lived - approximately 2 hours. In patients with operable tumors, Octreotide-MB may 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 long-term decrease in insulin levels in the blood.

In patients with tumors that overproduce growth hormone-releasing factor (somatoliberinomas), Octreotide-MB reduces the severity of symptoms of acromegaly. This is apparently due to inhibition of the secretion of growth hormone-releasing factor and GH itself. In the future, pituitary hypertrophy may decrease.

In patients undergoing pancreatic surgery, the use of Octreotide-MB 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, the use of the drug in combination with specific treatment (e.g., sclerosing therapy) resulted in more effective control of bleeding and early rebleeding, reduced transfusion volume, and improved 5-day survival. Although the exact mechanism of action of Octreotide-MB is not known, it is believed that the drug reduces organ blood flow by inhibiting vasoactive hormones such as VIP and glucagon.

Pharmacokinetics.

Absorption

After subcutaneous administration, octreotide is rapidly and completely absorbed. Maximum plasma concentrations are reached within 30 minutes.

Distribution

Binding to plasma proteins is 65%. Binding of octreotide to formed blood elements is extremely insignificant. Volume of distribution is 0.27 l/kg.

Breeding

The total clearance is 160 ml/min. The half-life after subcutaneous injection of the drug is 100 min. After intravenous administration, the drug is eliminated in two phases, with half-lives of 10 and 90 min, respectively. Most of the administered peptide dose is excreted in the feces, approximately 32% is excreted unchanged in the urine.

Kidney dysfunction

Impaired renal function does not affect the overall exposure (area under the concentration-time curve (AUC)) of subcutaneously administered octreotide.

Liver dysfunction

Elimination capacity may be reduced in patients with cirrhosis, but this does not apply to patients with hepatic steatosis.

Indication

Acromegaly, to control the main manifestations of the disease and reduce the level of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) in the blood plasma in cases where there is no sufficient effect of surgical treatment and radiotherapy. Octreotide-MB 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 radiotherapy until its effect is fully developed.

Relief of symptoms associated with endocrine tumors of the digestive tract and pancreas:

carcinoid tumors with the presence of carcinoid syndrome;

VIPomas (tumors characterized by hyperproduction of vasoactive intestinal peptide);

glucagonomas;

gastrinomas/Zollinger-Ellison syndrome, usually in combination with histamine H2 receptor antagonists or proton pump inhibitors;

insulinomas (for hypoglycemia control in the preoperative period, as well as for maintenance therapy);

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

Octreotide-MB is not an anticancer drug, therefore its use cannot contribute to the cure of 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).

Contraindication

Known hypersensitivity to octreotide or to any of the other ingredients of the drug.

Interaction with other medicinal products and other types of interactions

Dosage adjustments of medications such as β-adrenergic blockers, calcium channel blockers, or medications to control fluid and electrolyte balance may be necessary when octreotide is used concomitantly.

Dosage adjustments of insulin and hypoglycemic drugs may be necessary during concomitant treatment with octreotide.

Octreotide has been shown to reduce the intestinal absorption of cyclosporine and slow the absorption of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.

Limited published data suggest that somatostatin analogues may reduce the metabolic clearance of substances metabolised by cytochrome P450 enzymes, possibly due to inhibition of growth hormone. Since such an effect of octreotide cannot be excluded, caution should be exercised when using other drugs metabolised primarily by CYP 3A4 and with a narrow therapeutic index (such as quinidine, terfenadine).

Application features

General

Because growth hormone-secreting pituitary tumors can sometimes enlarge, causing serious complications (e.g., visual field defects), careful monitoring of all patients is important. If there is evidence of tumor enlargement, alternative treatments should be considered.

The therapeutic effect of lowering GH 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 also section "Use during pregnancy and lactation").

Thyroid function should be monitored in patients receiving long-term therapy with octreotide.

Liver function should be monitored during octreotide therapy.

Phenomena related to the cardiovascular system

Bradycardia has been reported uncommonly. Dosage adjustments of medications such as β-blockers, calcium channel blockers, and medications that control fluid or electrolyte balance may be necessary.

Cases of atrioventricular block (including complete atrioventricular block) have been observed in patients receiving high doses of continuous infusion (100 micrograms/hour) and in patients receiving octreotide as a bolus intravenously (50 micrograms bolus followed by 50 micrograms/hour continuous infusion). Therefore, the maximum dose of 50 micrograms/hour should not be exceeded (see section 4.2). Patients receiving high doses of intravenous octreotide should be monitored for cardiac abnormalities.

Phenomena related to the gallbladder

Cholelithiasis is frequently observed during treatment with octreotide and may be associated with cholecystitis and bile duct dilatation. Therefore, ultrasound examination of the gallbladder is recommended before starting therapy with Octreotide-MB and every 6-12 months during treatment.

Endocrine tumors of the gastrointestinal tract and pancreas

During the treatment of endocrine tumors of the gastrointestinal tract and pancreas, a sudden loss of symptomatic control with Octreotide-MB may occur occasionally, accompanied by a rapid return of severe symptoms. If the drug is discontinued, symptoms may worsen or recur.

Glucose metabolism

Due to its inhibitory effect on GH, glucagon and insulin, Octreotide-MB may disrupt glucose regulation. Postprandial glucose tolerance may be impaired, and in some cases, persistent hyperglycemia may occur as a result of chronic administration of the drug. Hypoglycemia may also occur.

In patients with insulinomas, octreotide, due to its greater relative ability to suppress GH and glucagon secretion compared to insulin, and due to the short duration of its inhibitory action on insulin, may increase the severity and prolong the duration of hypoglycemia. These patients should be closely monitored at the beginning of therapy with Octreotide-MB and at each dose change. Apparent fluctuations in blood glucose concentrations can be reduced by more frequent administration of smaller doses.

The dependence of patients with type I diabetes mellitus on insulin or oral hypoglycemic agents may be reduced by the administration of Octreotide-MB. In patients without diabetes mellitus and with type II diabetes mellitus with partially intact insulin reserve, the administration of Octreotide-MB may increase postprandial glycemia. Careful monitoring of glucose tolerance and antidiabetic treatment is recommended.

Esophageal varicose veins

Since episodes of bleeding from esophageal varices are associated with an increased risk of developing insulin-dependent diabetes or changes in insulin requirements in patients with pre-existing diabetes, appropriate monitoring of blood glucose levels is necessary.

Local reactions

In a 52-week toxicity study in rats, predominantly males, sarcomas were observed at the subcutaneous injection site only at the highest dose (approximately 8 times the maximum human dose based on body surface area). In a 52-week toxicity study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. There have been no reports of injection site tumours in patients treated with octreotide for up to 15 years. All information available to date indicates that the findings in rats are species-specific and have no relevance to humans.

Food

Octreotide-MB may impair the absorption of dietary fat in some patients.

Reduced vitamin B12 levels and abnormal Schilling test results have been observed in some patients treated with octreotide. Patients with a history of vitamin B12 deficiency should have their vitamin B12 levels monitored during therapy with Octreotide-MB.

Pancreas function:

Sodium content

Octreotide-MB contains less than 1 mmol (23 mg) of sodium, i.e. the medicine is essentially sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

There are limited data (less than 300 outcomes) on octreotide treatment in pregnant women, but in approximately one third of cases the pregnancy outcome is unknown. Most reports have been received from postmarketing use of octreotide, of which more than 50% involved use in pregnant patients with acromegaly. Most women received octreotide during the first trimester of pregnancy at doses of 100–1200 μg/day as subcutaneous octreotide or 10–40 mg/month as octreotide LAR.

Congenital anomalies have been reported in approximately 4% of pregnancies with known outcomes. In these cases, no association with octreotide has been found.

Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of octreotide during pregnancy.

Breastfeeding period

Breastfeeding is not recommended during treatment with Octreotide-MB. It is not known whether octreotide is excreted in human milk. In animal studies, excretion of octreotide into breast milk has been observed.

Fertility

It is not known whether octreotide affects human fertility. Delayed testicular descent has been observed in male offspring of females administered octreotide during pregnancy and lactation. However, in experimental studies, octreotide did not affect fertility in male and female rats at doses up to 1 mg/kg body weight per day.

Ability to influence reaction speed when driving vehicles or other mechanisms

Octreotide-MB has no or negligible influence on the ability to drive and use machines. Patients should be advised to exercise caution when driving or operating machinery if they experience dizziness, asthenia/fatigue or headache during treatment with octreotide.

Method of administration and doses

Dosage

In acromegaly, the drug is initially administered subcutaneously at 0.05-0.1 mg every 8 or 12 hours. Subsequently, dose selection should be based on monthly determinations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) concentrations in the blood, analysis of clinical symptoms and tolerability of the drug (target hormone concentrations in the blood are: GH - less than 2.5 ng/ml, IGF-1 - within normal limits). For most patients, the optimal daily dose is 0.3 mg. The maximum daily dose is 1.5 mg per day, which should not be exceeded. In patients receiving a stable dose of octreotide, GH and IGF-1 concentrations should be determined every 6 months.

If within 3 months of treatment with Octreotide-MB there is no sufficient decrease in GH 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 in an initial dose of 0.05 mg 1-2 times a day. Subsequently, depending on the achieved clinical effect, as well as the effect on the levels 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 tolerability, the dose of the drug can be gradually increased to 0.1-0.2 mg 3 times a day. In exceptional cases, higher doses may be required.

Maintenance doses of the drug should be selected individually.

If no improvement occurs within 1 week of treatment with Octreotide-MB at the maximum tolerated dose, therapy should be discontinued.

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

In case of bleeding from esophageal varices, the drug is administered at a dose of 25 mcg/hour by continuous intravenous infusion for 5 days. Octreotide-MB can be diluted with 0.9% sodium chloride solution.

In patients with cirrhosis and bleeding from gastric and esophageal varices, good responsiveness to octreotide was noted when receiving a stable dose of the drug up to 50 mcg/hour as a continuous intravenous infusion for 5 days.

Use in patients with renal impairment

Renal impairment does not affect the AUC of octreotide administered by subcutaneous injection. Therefore, no dose adjustment is required.

Use in patients with hepatic impairment

In patients with cirrhosis of the liver, the half-life of the drug may increase, requiring adjustment of the maintenance dose.

Use in elderly patients

There is no evidence of reduced tolerability or the need for dosage adjustment for elderly patients treated with Octreotide-MB.

Method of application

Octreotide-MB can be administered directly by subcutaneous injection or by intravenous infusion after dilution.

Subcutaneous injections

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 administering the drug, and any remaining drug should be discarded.

Intravenous infusions

Parenteral medicinal products should be inspected visually for discoloration and particulate matter prior to administration. The product must be diluted prior to administration by intravenous infusion. Octreotide-MB is chemically and physically stable for 24 hours in sterile saline or sterile 5% dextrose (glucose) in water. However, as Octreotide-MB may affect glucose homeostasis, saline is preferred to dextrose. The diluted solution has been physically and chemically stable for at least 24 hours not above 25°C. From a microbiological safety point of view, the diluted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Children.

The use of Octreotide-MB in children is contraindicated due to the lack of clinical experience.

Overdose

There are limited reports of accidental overdose with octreotide in adults and children. In adults, doses ranged from 2400 to 6000 mcg/day administered by continuous infusion (100 to 250 mcg/hour) or subcutaneously (1500 mcg 3 times daily). The following adverse events have been reported: arrhythmia, hypotension, cardiac arrest, cerebral hypoxia, pancreatitis, hepatic steatosis, diarrhea, weakness, somnolence, weight loss, hepatomegaly, and lactic acidosis.

In children, octreotide doses ranged from 50 to 3000 mcg/day and were administered by continuous infusion (2.1 to 500 mcg/hour) or subcutaneously (50 to 100 mcg). The only adverse event was mild hyperglycemia.

Cases of atrioventricular block (including complete atrioventricular block) have been observed in patients receiving high doses of continuous infusion (100 micrograms/hour) and in patients receiving octreotide bolus intravenously (50 micrograms bolus followed by 50 micrograms/hour continuous infusion).

No unexpected adverse events were observed in cancer patients receiving octreotide doses of 3000-30000 mcg/day in divided doses subcutaneously.

Treatment: symptomatic therapy.

Side effects

Brief description of the safety profile of the drug

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

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

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

Pain or a sensation of sharp pain, tingling or burning at the site of subcutaneous injection with redness and swelling rarely lasts longer than 15 minutes. Local discomfort can be reduced by bringing the solution to room temperature before injection or by injecting a smaller volume of a more concentrated solution.

Although fecal fat excretion may increase, there is no evidence that long-term treatment with Octreotide-MB can lead to the development of trophic deficiencies due to malabsorption.

Side effects from the digestive tract can be reduced by not eating before or immediately after subcutaneous administration of Octreotide-MB; it is recommended to administer the drug between meals or at bedtime.

Acute pancreatitis has been reported rarely. This phenomenon usually occurs within the first hours or days of subcutaneous administration of Octreotide-MB and disappears after discontinuation of the drug. In addition, patients receiving prolonged subcutaneous administration of Octreotide-MB may develop pancreatitis due to cholelithiasis.

ECG changes such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave enlargement, and nonspecific ST-T wave changes have been observed in patients with acromegaly and carcinoid syndrome. The relationship between these events and octreotide acetate has not been established, as many of these patients have underlying cardiac disease (see section 4.4).

Adverse drug reactions (Table 1) are ranked by frequency using the following convention: 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 grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1

Adverse drug reactions reported during clinical trials

Post-marketing studies

The adverse reactions presented in Table 2 were reported voluntarily; however, it is not always possible to reliably establish the frequency or causal relationship to the use of the drug.

Table 2

Adverse drug reactions described in spontaneous reports

Description of selected adverse reactions

Biliary tract reactions

Somatostatin analogues have been shown to inhibit gallbladder contractility and reduce bile secretion, which can lead to gallbladder disease and sludge formation. Gallstones have been reported in 15–30% of patients treated with octreotide for long periods of time. The incidence of this condition in the general population (aged 40–60 years) is 5–20%. Gallstone formation is usually asymptomatic. If symptoms occur, either bile acid-based therapy or surgical intervention should be considered.

Gastrointestinal disorders

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

It is known that with continued treatment with the drug, the frequency of gastrointestinal adverse reactions decreases.

Gastrointestinal side effects can be reduced by not eating before or immediately after subcutaneous administration of octreotide; it is recommended to administer the drug between meals or at bedtime.

Hypersensitivity and anaphylactic reactions

In the post-marketing period, cases of hypersensitivity and allergic reactions have been reported. If such reactions occur, they mainly affect the skin, rarely the oral cavity and respiratory tract. Isolated cases of anaphylactic shock have been reported.

Local reactions

Pain or a tingling, prickling, or burning sensation at the site of subcutaneous injection with redness and swelling rarely lasts longer than 15 minutes. Local discomfort can be reduced by bringing the solution to room temperature before injection or by injecting a smaller volume of a more concentrated solution.

Metabolic and nutritional disorders

Although fecal fat excretion may increase, there is currently no evidence that long-term treatment with octreotide can lead to the development of trophic deficiencies due to malabsorption.

Pancreatic disorders

Cardiovascular system disorders

Bradycardia is a common adverse reaction with somatostatin analogues. ECG changes such as QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, early R wave enlargement, and nonspecific ST-T wave changes have been observed in patients with acromegaly and carcinoid syndrome. The relationship between these events and octreotide has not been established, as many of these patients have underlying cardiac disease (see section 4.4).

Thrombocytopenia

In the post-marketing period, cases of thrombocytopenia have been reported, particularly with octreotide (intravenous) treatment in patients with liver cirrhosis. The phenomenon resolved after discontinuation of the drug.

Expiration date

5 years.

During use, ampoules can be kept at room temperature for up to 2 weeks.

Storage conditions

Store in the original packaging at a temperature of 2°C to 8°C.

Keep out of reach of children.

Incompatibility

Octreotide acetate is unstable in solutions for total parenteral nutrition.

Do not use solvents other than those listed in the Dosage and Administration section. Octreotide is unstable in solutions for total parenteral nutrition.

Packaging

1 ml in an ampoule.

5 ampoules in a cardboard pack.

Vacation category

According to the recipe.

Producer

Bendalis GmbH

Bendalis GmbH

Location of the manufacturer and address of its place of business.

Keltenring 17, 82041 Oberhaching, Germany

Keltenring 17, 82041 Oberhaching, Germany

Applicant

M.Biotech Ltd.

M.Biotech Ltd

Applicant's location

Gladstone House, 77-79 High Street, Egham TV20 9GY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom