Octra

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OКТRA® (OCTRA)

Composition:

Active substance: octreotide;

1 ml of solution contains 0.1 mg of octreotide acetate, calculated as 100% substance;

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

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group. Hormonal preparations for systemic use, excluding sex hormones and insulin. Hypothalamic and pituitary hormones and their analogues. Hypothalamic hormones. Somatostatin and analogues. Octreotide. ATC code H01CB02.

Pharmacological properties.

Pharmacodynamics.

OCTREO® – a synthetic octapeptide, which is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but with significantly longer duration of action. The drug suppresses pathologically increased secretion of growth hormone (GH), as well as peptides and serotonin produced by the gastroenteropancreatic endocrine system.

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

In healthy volunteers, octreotide suppresses: growth hormone secretion stimulated by arginine, physical exercise, and insulin-induced hypoglycemia; food-stimulated secretion of insulin, glucagon, gastrin, and other peptides of the gastroenteropancreatic endocrine system, as well as arginine-stimulated secretion of insulin and glucagon; thyrotropin secretion induced by thyroliberin.

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

In patients with acromegaly, octreotide reduces plasma concentrations of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Suppression of GH by 50% or more is observed in 90% of patients; a reduction in plasma GH levels to less than 5 ng/mL is achieved in approximately half of patients. In most patients with acromegaly, octreotide significantly reduces the severity of symptoms such as headache, skin and soft tissue swelling, hyperhidrosis, joint pain, and paresthesia. In patients with large GH-secreting pituitary adenomas, treatment with octreotide may lead to some reduction in tumor size.

In patients with functional endocrine tumors of the gastrointestinal tract (GI) and pancreas, octreotide, due to its various endocrine effects, influences several clinical manifestations of the disease. Clinical and symptomatic improvement is observed in patients who still have symptoms related to tumors despite prior treatment, which may include surgical interventions, hepatic artery embolization, and various chemotherapy regimens, for example, streptozotocin and 5-fluorouracil.

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

In tumors characterized by hyperproduction of vasoactive intestinal peptide (VIP), the use of octreotide leads in most patients to a reduction in the severe secretory diarrhea typical of this condition, thereby improving the patient's quality of life. Concurrently, associated electrolyte imbalances, such as hypokalemia, are reduced, allowing discontinuation of enteral and parenteral fluid and electrolyte replacement. Computed tomography data indicate that in some patients, tumor growth slows or stops, and even tumor shrinkage may occur, particularly in liver metastases. Clinical improvement is usually accompanied by a reduction (even to normal levels) in plasma vasoactive intestinal peptide concentration.

In glucagonomas, octreotide use in most cases leads to a marked reduction in the necrolytic migratory erythema characteristic of this condition. Octreotide has no significant effect on mild diabetes mellitus, which is commonly observed in glucagonomas and usually does not reduce the need for insulin or oral hypoglycemic agents. In patients suffering from diarrhea, octreotide helps reduce it, accompanied by an increase in body weight. With octreotide use, a rapid decrease in plasma glucagon concentration is often observed, although this effect does not persist during long-term treatment. At the same time, symptomatic improvement remains stable over a prolonged period.

In patients with gastrinomas/Zollinger–Ellison syndrome, therapy with proton pump inhibitors or H2-receptor antagonists may reduce gastric acid secretion. However, diarrhea, another major symptom, may not be sufficiently alleviated by proton pump inhibitors or H2-receptor blockers. In some patients, octreotide may further reduce gastric acid hypersecretion and alleviate symptoms, including diarrhea, by suppressing elevated gastrin levels.

In patients with insulinomas, octreotide reduces the level of immunoreactive insulin in the blood. This effect, however, may be transient—approximately 2 hours. In patients with resectable tumors, octreotide may help restore and maintain normoglycemia in the preoperative period. In patients with unresectable benign and malignant tumors, glycemic control may improve without a concurrent sustained reduction in blood insulin levels.

In patients with tumors hyperproducing growth hormone-releasing factor (somatoliberinomas), octreotide reduces the severity of acromegaly symptoms. This is evidently due to suppression of growth hormone-releasing factor and growth hormone itself. Subsequently, pituitary hypertrophy may decrease.

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

In patients with bleeding from esophageal and gastric varices due to liver cirrhosis, the use of octreotide in combination with specific treatment (e.g., sclerotherapy) leads to more effective control of bleeding and prevention of early rebleeding, reduced transfusion requirements, and improved five-day survival. Although the exact mechanism of action of octreotide is not fully established, it is believed that the drug reduces splanchnic blood flow by inhibiting vasodilatory hormones such as VIP and glucagon.

Pharmacokinetics.

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

Distribution. Protein binding in plasma is 65%. Binding of octreotide to blood cells is negligible. Volume of distribution is 0.27 L/kg.

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

Special patient populations

Patients with impaired renal function

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

Patients with impaired hepatic function

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

Clinical characteristics.

Indications.

• Acromegaly – for control of the main manifestations of the disease and reduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) plasma levels in cases where surgical treatment and radiotherapy have not provided sufficient effect. Octrea® is also indicated for treatment of patients with acromegaly who have refused surgery or have contraindications to it, as well as for short-term treatment during intervals between courses of radiotherapy until its full effect develops.
• Relief of symptoms associated with endocrine tumors of the gastrointestinal tract (GI) and pancreas:
  • carcinoid tumors with 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 control of hypoglycemia in the preoperative period, as well as for maintenance therapy);
  • somatostatinomas (tumors characterized by hyperproduction of growth hormone-releasing factor).

Octrea® is not an antineoplastic agent, and its use cannot lead to cure in this category of patients.

• Prevention of complications following pancreatic surgery.
• Stopping bleeding and prevention of recurrent bleeding from esophageal varices in patients with liver cirrhosis (in combination with specific therapeutic measures, e.g., endoscopic sclerotherapy).

Contraindications.

Known hypersensitivity to octreotide or to any of the excipients of the drug.

Interaction with other medicinal products and other forms of interactions.

Dosage adjustment of drugs such as beta-blockers, calcium channel blockers, or agents used to control fluid and electrolyte balance may be required when administered concomitantly with octreotide.

Dosage adjustment of insulin and antidiabetic agents may be required when administered concomitantly with octreotide.

It has been established that octreotide reduces intestinal absorption of cyclosporine and delays absorption of cimetidine.

Concomitant administration of octreotide and bromocriptine increases bioavailability of bromocriptine.

Limited published data suggest that somatostatin analogs may reduce metabolic clearance of substances metabolized by cytochrome P450 enzymes, possibly due to inhibition of GH secretion. Since such an effect cannot be ruled out for octreotide, caution should be exercised when coadministering other drugs that are primarily metabolized by CYP3A4 and have a narrow therapeutic index (e.g., quinidine, terfenadine).

Special precautions for use.

General

Since GH-secreting pituitary tumors may occasionally enlarge, causing serious complications (e.g., visual field defects), careful monitoring of all patients is essential. If signs of tumor enlargement occur, the need for alternative treatment modalities 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 reproductive age receiving octreotide therapy should be advised to use adequate contraceptive methods (see also section "Use during pregnancy or breastfeeding").

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

Liver function should be monitored during octreotide therapy.

Cardiovascular effects

Bradycardia has been frequently reported. Dose adjustments of medications such as beta-blockers, calcium channel blockers, and agents affecting fluid and electrolyte balance may be required.

Cardiovascular disorders

Cases of atrioventricular block (including complete atrioventricular block) have been observed in patients receiving continuous high-dose infusions (100 micrograms/hour) and in patients receiving intravenous bolus octreotide (50 micrograms bolus followed by 50 micrograms/hour continuous infusion). Therefore, the maximum dose of 50 micrograms/hour should not be exceeded (see section "Dosage and administration"). Patients receiving high-dose intravenous octreotide should be under appropriate cardiac monitoring.

Gallbladder-related events

Cholelithiasis is frequently observed during octreotide treatment and may be associated with cholecystitis and bile duct dilation. In addition, cases of cholangitis as a complication of cholelithiasis have been reported in patients receiving octreotide in the post-marketing period. Therefore, ultrasound examination of the gallbladder is recommended before initiating octreotide therapy and approximately every 6–12 months during treatment.

Gastrointestinal and pancreatic endocrine tumors

During treatment of gastrointestinal and pancreatic endocrine tumors, a sudden loss of symptomatic control by Octra® may rarely occur, accompanied by rapid recurrence of severe symptoms. Discontinuation of the drug may lead to worsening or recurrence of symptoms.

Pancreatic function

Exocrine pancreatic insufficiency (EPI) has been observed in some patients receiving octreotide therapy for gastroenteropancreatic neuroendocrine tumors. Symptoms of EPI may include steatorrhea, loose stools, abdominal bloating, and weight loss. Screening and appropriate management of EPI according to clinical guidelines should be considered in symptomatic patients.

Glucose metabolism

Due to its inhibitory effects on growth hormone, glucagon, and insulin, Octra® may affect glucose regulation. Glucose tolerance after food intake may be impaired, and in some cases, chronic administration of the drug may lead to persistent hyperglycemia. Hypoglycemia may also occur.

In insulinoma patients, octreotide may prolong and intensify hypoglycemia due to its relatively greater potency in suppressing GH and glucagon secretion compared to insulin, as well as its relatively short inhibitory effect on insulin secretion. These patients should be closely monitored at the start of Octra® therapy and with each dosage adjustment. Fluctuations in blood glucose concentration may be minimized by more frequent administration of lower doses.

The requirement for insulin or oral hypoglycemic agents in patients with type I diabetes may decrease under the influence of Octra®. In patients without diabetes or with type II diabetes who have partially intact insulin reserves, administration of Octra® may lead to increased postprandial glycemia. Careful monitoring of glucose tolerance and antidiabetic therapy is recommended.

Esophageal varices

Since bleeding from esophageal varices may increase the risk of developing insulin-dependent diabetes and may alter insulin requirements in diabetic patients, appropriate monitoring of blood glucose concentration is mandatory.

Local reactions

In a 52-week toxicity study in rats, sarcomas were observed at the subcutaneous injection site, predominantly in males, but 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 changes were observed at the injection site. There are no reports of tumors at the injection site in patients treated with octreotide for up to 15 years. All available data suggest that the findings in rats are species-specific and not relevant to the use of the drug in humans.

Nutrition

Octreotide may impair fat absorption from food in some patients.

Decreased vitamin B12 levels and abnormal Schilling test results have been observed in some patients receiving octreotide therapy. Vitamin B12 levels should be monitored in patients with a history of vitamin B12 deficiency during octreotide treatment.

The medicinal product contains less than 1 mmol/dose of sodium, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

There is limited data (fewer than 300 outcomes) on octreotide use in pregnant women, but pregnancy outcomes are unknown in approximately one-third of cases. Most reports were from post-marketing use of octreotide, and more than 50% of the pregnant women were treated for acromegaly. Most women received octreotide during the first trimester at doses of 100–1200 mcg/day subcutaneously or 10–40 mg/month as Sandostatin® LAR. Congenital anomalies were reported in approximately 4% of pregnancies with known outcomes. No association with octreotide exposure was established in these cases.

Animal studies revealed no direct or indirect harmful effects on the reproductive system.

As a precautionary measure, it is advisable to avoid administration of Octra® during pregnancy.

Breastfeeding

Breastfeeding is not recommended during treatment with this medicinal product. It is unknown whether octreotide passes into human breast milk. Excretion of octreotide into breast milk has been observed in animal studies.

Fertility

It is unknown whether octreotide affects human fertility. In male offspring of females treated with octreotide during pregnancy and lactation, delayed testicular descent was observed. 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 drive and use machines.

Octra® has no or negligible influence on the ability to drive or operate machinery. Patients should be advised to exercise caution when driving or operating machinery if they experience dizziness, asthenia/fatigue, or headache during treatment.

Method of Administration and Dosage.

Dosage

In acromegaly, the drug should initially be administered subcutaneously at a dose of 0.05–0.1 mg every 8 or 12 hours. Subsequent dosage selection should be based on monthly measurements of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, clinical symptom assessment, and drug tolerability (target hormone levels: GH < 2.5 ng/mL, IGF-1 within normal range). For most patients, the optimal daily dose is 0.3 mg. The maximum daily dose is 1.5 mg, which should not be exceeded. In patients receiving a stable dose of Octre® drug, GH and IGF-1 levels should be monitored every 6 months.

If, after 3 months of treatment, there is no sufficient reduction in GH levels and no improvement in clinical symptoms, therapy should be discontinued.

In gastrointestinal and pancreatic endocrine tumors, the drug should be administered subcutaneously at an initial dose of 0.05 mg 1–2 times daily. Subsequently, depending on the achieved clinical effect, influence on tumor-produced hormone levels (in carcinoid tumors—on urinary excretion of 5-hydroxyindoleacetic acid), and tolerability, the dose may be gradually increased to 0.1–0.2 mg three times daily. Higher doses may be required in exceptional cases.

Maintenance doses should be individually adjusted.

If no improvement occurs within one week of treatment with Octre® at the maximum tolerated dose in carcinoid tumors, further therapy is not recommended.

For prevention of complications after pancreatic surgery, administer the drug subcutaneously at 0.1 mg three times daily for 7 consecutive days, starting on the day of surgery (at least 1 hour before laparotomy).

In bleeding from esophageal varices, administer the drug at a dose of 25 mcg/hour via continuous intravenous infusion for 5 days. Octre® can be diluted with 0.9% sodium chloride solution.

In patients with cirrhosis and bleeding from gastric and esophageal varices, good response to Octre® has been observed with a stable dose of up to 50 mcg/hour administered as a continuous intravenous infusion for 5 days.

Use in patients with renal impairment

Renal impairment does not affect the overall exposure (area under the concentration-time curve [AUC]) of octreotide administered by subcutaneous injection. Therefore, dosage adjustment of Octre® is not required.

Use in patients with hepatic impairment

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

Use in elderly patients

There is no evidence of reduced tolerability or need for dosage adjustment in elderly patients treated with Octre®.

Method of Administration

Octre® can be administered directly by subcutaneous injection or by intravenous infusion after dilution.

The ampoule (0.1 mg/1 mL) is intended for single use only. It should be opened immediately before administration, and any unused content should be discarded.

Subcutaneous administration. A patient intending to self-administer the drug via subcutaneous injection must receive precise instructions from a physician or nurse.

To reduce local discomfort, it is recommended to wait until the solution reaches room temperature before administration. Repeated injections at the same site with short intervals should be avoided.

Intravenous infusion. Parenteral medicinal products should be visually inspected for discoloration and presence of particulate matter before administration. Before intravenous infusion, the drug must be diluted. Octre® maintains chemical and physical stability for 24 hours in sterile physiological saline (sodium chloride 0.9%) or sterile 5% dextrose (glucose) in water. However, since Octre® may affect glucose homeostasis, physiological saline is preferred over dextrose solution. The diluted solution remains physically and chemically stable for at least 24 hours at temperatures up to 25°C. From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user.

Children

Octre® is contraindicated in children due to lack of clinical experience.

Overdose

A limited number of accidental overdoses of octreotide in adults and children have been reported. In adults, doses ranged from 2400 to 6000 mcg/day administered via continuous infusion (100–250 mcg/hour) or subcutaneously (1500 mcg three times daily). Adverse events reported include arrhythmia, arterial hypotension, cardiac arrest, cerebral hypoxia, pancreatitis, hepatic steatosis, diarrhea, weakness, somnolence, weight loss, hepatomegaly, and lactic acidosis. Atrioventricular block (including complete atrioventricular block) has been reported in patients receiving high-dose continuous infusion (100 mcg/hour) and/or bolus intravenous administration of octreotide (50 mcg bolus followed by 50 mcg/hour continuous infusion).

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

In cancer patients receiving octreotide doses of 3000–30000 mcg/day administered subcutaneously in divided doses, no unexpected adverse events were observed.

Treatment: symptomatic.

Patients who have received intravenous octreotide at doses exceeding the recommended dose are at increased risk of developing higher-degree atrioventricular blocks and should be under appropriate cardiac monitoring.

Adverse Reactions

Summary of the drug's safety profile

The most common adverse reactions associated with octreotide treatment involve the gastrointestinal tract, nervous system, liver and gallbladder, as well as metabolism and nutrition.

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

The information on adverse reactions listed in Table 1 was obtained from clinical trials of octreotide.

Adverse reactions are listed by frequency category: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated case reports. Within each frequency group, adverse reactions are listed according to severity.

Table 1

Adverse reactions to octreotide reported in clinical trials

Post-marketing studies

Adverse reactions listed in Table 2 have been reported voluntarily in spontaneous reports, and therefore, it is not always possible to reliably determine their frequency or establish a causal relationship with the use of the drug.

Table 2

Adverse reactions to octreotide reported in spontaneous reports

Description of individual adverse reactions

Biliary system disorders

Somatostatin analogues have been shown to inhibit gallbladder motility and reduce bile secretion, which may lead to gallbladder pathology and sludge formation. Gallstone development has been observed in 15–30% of patients receiving long-term octreotide treatment. The prevalence of this condition in the general population (aged 40–60 years) is 5–20%. Gallstone formation is usually asymptomatic. If symptoms occur, therapy aimed at dissolving stones with bile acids or surgical intervention should be considered.

Gastrointestinal disorders

In isolated cases, gastrointestinal adverse reactions may mimic acute intestinal obstruction — progressive abdominal distension, severe epigastric pain, abdominal tenderness and rigidity.

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

Gastrointestinal side effects may be minimized by avoiding food intake before or immediately after subcutaneous octreotide injection; the drug should be administered between meals or at bedtime.

Hypersensitivity and anaphylactic reactions

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

Local reactions

Pain or sensations of tingling, pricking, or burning at the site of subcutaneous injection, accompanied by redness and swelling, rarely last longer than 15 minutes. Local discomfort may be reduced by allowing the solution to reach room temperature before injection or by using a smaller volume of a more concentrated solution.

Metabolism and nutrition disorders

Although fecal fat excretion may increase, there are currently no data indicating that long-term octreotide treatment leads to nutritional deficiencies due to malabsorption.

Pancreatic disorders

Very rarely, acute pancreatitis has been reported. This phenomenon usually occurs within the first hours or days after subcutaneous octreotide administration and resolves upon discontinuation of the drug. Additionally, pancreatitis may develop in patients receiving long-term subcutaneous octreotide due to gallstone disease.

Cardiovascular system disorders

Bradycardia is a common adverse reaction during treatment with somatostatin analogues. In patients with acromegaly and carcinoid syndrome, the following ECG changes have been observed: prolongation of the QT interval, axis deviation, early repolarization, low voltage, R/S transition, early increase of R wave, and non-specific ST-T wave changes. The relationship between these findings and octreotide has not been established, as many of these patients have underlying cardiovascular disease (see section "Special precautions").

Thrombocytopenia

During the post-marketing period, cases of thrombocytopenia have been reported, particularly in patients with liver cirrhosis receiving octreotide (intravenously). This phenomenon resolved after discontinuation of the drug.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

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

Do not freeze. Keep out of reach of children.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except as specified in the section "Dosage and administration". Octreotide is unstable in solutions for total parenteral nutrition.

Packaging. 1 ml in a vial. 5 vials per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of the place of business.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.