Octreotide,. 50 µg/ml 1 ml 5 pcs

Octreotide is a synthetic analog of somatostatin, which is a derivative of the natural hormone somatostatin and has similar pharmacological effects to it, but a much longer duration of action. Octreotide suppresses growth hormone secretion, both pathologically increased and induced by arginine, exercise and insulin hypoglycemia. The drug also suppresses insulin, glucagon, gastrin, and serotonin secretion, both pathologically elevated and induced by food intake; it also suppresses arginine-stimulated insulin and glucagon secretion. Octreotide suppresses thyrotropin secretion induced by thyreoliberin. Unlike somatostatin, octreotide suppresses growth hormone secretion to a greater extent than insulin secretion, and its administration is not accompanied by subsequent hormone hypersecretion (such as growth hormone in acromegaly patients).

In patients with acromegaly, octreotide reduces plasma concentrations of growth hormone and insulin-like growth factor (IGF-1). Decrease of growth hormone concentration by 50% or more is noted in 90% of patients, and the value of growth hormone concentration of not less than 5 ng/ml is reached in about half of patients. In most patients with acromegaly, octreotide reduces the severity of headache, soft tissue swelling, hyperhidrosis, joint pain and paresthesias. In patients with large pituitary adenomas, treatment with Octreotide may lead to some reduction in tumor size.

In secreting tumors of the gastroenteropancreatic endocrine system in cases of ineffective therapy (surgery, hepatic artery embolization, chemotherapy, including streptozotocin and fluorouracil) administration of Octreotide can lead to improvement of the disease course. For example, in carcinoid tumors, administration of Octreotide can lead to a reduction in the severity of the feeling of blood rush to the face, diarrhea, which in many cases is accompanied by a decrease in plasma serotonin concentration and renal excretion of 5-hydroxyindoleacetic acid.

In tumors characterized by hyperproduction of vasoactive intestinal peptide (VIPOM), use of octreotide leads in most patients to reduction of severe secretory diarrhea and, accordingly, improvement of patient’s quality of life. At the same time there is a reduction of concomitant electrolyte balance disorders, such as hypokalemia, which allows to cancel enteral and parenteral administration of fluids and electrolytes.

In some patients the progression of the tumor is slowed or stopped, its size and the size of liver metastases decrease. Clinical improvement is usually accompanied by a decrease in plasma concentration of vasoactive intestinal peptide (VIP) or its normalization. In glucagonomas, use of Octreotide leads to a reduction of erythema migrans. Octreotide has no significant effect on the severity of hyperglycemia in diabetes mellitus, and the need for insulin or oral hypoglycemic agents usually remains unchanged. The drug causes reduction of diarrhea, which is accompanied by an increase in body weight.

While decrease in plasma glucagon concentration under the influence of Octreotide is transient, the clinical improvement remains stable during the whole period of using the drug. In patients with gastrinomas/Zollinger-Ellison syndrome when using Octreotide as monotherapy or in combination with proton pump inhibitors or H₂-histamine receptor blockers, a decrease of hydrochloric acid hypersecretion in the stomach, decrease of gastrin concentration in blood plasma, and reduction of diarrhea and flushes severity are possible. In patients with insulinomas octreotide decreases the level of immunoreactive insulin in blood (this effect may be short-lived – 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 concomitant prolonged decrease in blood insulin levels.

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

In bleeding from esophageal and gastric varices in cirrhotic patients, the use of octreotide in combination with specific treatments (e.g., sclerosing therapy) leads to more effective bleeding arrest and early rebleeding, reduced transfusion volume and improved 5-day survival. The mechanism of action of octreotide is thought to be related to reduction of organ blood flow through suppression of vasoactive hormones such as VIP and glucagon.

Pharmacokinetics

Intake

After oral administration, octreotide is quickly and completely absorbed. T_max of Octreotide in plasma is within 30 min.

Distribution

The binding to plasma proteins is 65%. The binding of octreotide to blood cells is extremely insignificant. V_d is 0.27 l/kg.

Excretion

T_1/2 after p/c administration of Octreotide is 100 min. After IV administration, excretion of Octreotide occurs in 2 phases, with T_1/2 of 10 and 90 min, respectively. Most part of octreotide is excreted through the intestine, about 32% – unchanged by the kidneys. Total clearance is 160 ml/min.

Indications

Active ingredient

Composition

Active ingredient:

octreotide acetate;

Associates

sodium chloride;

water for injection

How to take, the dosage

Subcutaneously, intravenously with a drip.

In acromegaly, by injection, in a dose of 300 mcg at 8 or 12-hour intervals. This dose is used if initial therapy is ineffective (Octreotide, solution for intravenous and intravenous injection, 50-100 mcg at 8 or 12-hour intervals). Ineffectiveness of initial therapy is evaluated based on monthly blood concentrations of growth hormone (target concentration: growth hormone)

In patients receiving Octreotide at a stable dose, growth hormone concentrations should be determined every 6 months. If after 3 months of treatment with Octreotide there is not sufficient decrease of growth hormone concentration and improvement of clinical picture of the disease, the therapy should be discontinued.

In tumors of the gastroenteropancreatic endocrine system – p/c, in a dose of 300 mcg 1-2 times a day. This dose is used if the initial therapy (Octreotide, solution for intravenous and intravenous injection, 50 mcg 1-2 times a day with gradual increase to 100-200 mcg 3 times a day) is ineffective. The ineffectiveness of initial therapy is evaluated based on the achieved clinical effect, the effect on the concentration of hormones produced by the tumor (in the case of carcinoid tumors, the effect on renal excretion of 5-hydroxyindoleacetic acid) and tolerability. In exceptional cases it is allowed to prescribe the patient a dose exceeding 600 mcg/day, the drug dose can be gradually increased to 300-600 mcg 3 times a day. Maintenance doses of the drug should be selected individually. In carcinoid tumors, if therapy with octreotide in the maximum tolerated dose for 1 week has not been effective, treatment should not be continued.

In case of bleeding from variceal veins of the esophagus and stomach, by IV drip, at a rate of 25 mcg/h for 5 days.

Particular patient groups

There is currently no evidence to suggest that the tolerability of octreotide is reduced in the elderly and a change in dosing regimen is required for them.

Adjustment of the maintenance dose in patients with impaired liver function is recommended.

In patients with impaired renal function no dosing adjustments for octreotide are required.

The experience with octreotide in children is limited.

The rules for use of the drug

Introduction by injection. Patients who self-administer octreotide b/c should obtain detailed instructions from their physician or nurse. The solution should be warmed up to room temperature before injection to reduce discomfort at the injection site. The drug should not be injected into the same place at short intervals. Ampoules should be opened immediately before injecting; the unused amount of solution should be discarded.

Intravenous drip administration. If it is necessary to administer Octreotide by IV drip injection, the contents of one ampoule containing 600 µg of the active substance should be diluted in 60 ml of 0.9% sodium chloride solution. Octreotide remains physically and chemically stable in sterile 0.9% sodium chloride solution or 5% dextrose solution in water at temperatures below 25°C for 24 h. However, since octreotide may affect glucose metabolism, it is preferable to use 0.9% sodium chloride solution. Before IV administration, the ampoule should be carefully inspected for discoloration of the solution and presence of foreign particles.

In order to avoid microbial contamination, diluted solutions should be used immediately after preparation. If the solution will not be used immediately, it should be stored at 2-8 °C. The solution should be warmed to room temperature before administration. The total time between dilution, storage in the refrigerator and completion of solution administration should not exceed 24 h.

Interaction

It reduces absorption of cyclosporine, slows down absorption of cimetidine. It is necessary to correct the dosing regimen of concomitantly used diuretics, beta-adrenoblockers, BCC, oral hypoglycemic drugs, glucagon.

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

Decreases the metabolism of substances metabolized with the participation of cytochrome P450 system enzymes (may be due to inhibition of growth hormone).

Because these effects of Octreotide cannot be excluded, caution should be exercised when prescribing drugs that are metabolized by the cytochrome P450 system and have a narrow range of therapeutic concentrations (e.g. quinidine, terfenadine).

Special Instructions

In pituitary tumors secreting growth hormone, patients receiving octreotide should be closely monitored, as tumors may increase in size and develop serious complications such as narrowing of the visual fields. In these cases other treatment options should be considered.

Because a decrease in growth hormone levels and normalization of IGF-1 levels with octreotide therapy may lead to restoration of fertility in women with acromegaly, patients of childbearing age should use reliable contraception when using the drug.

When prescribing Octreotide for an extended period of time, thyroid function should be monitored.

If bradycardia develops with octreotide, doses of beta-adrenoblockers, BCCs or drugs affecting the water-electrolyte balance may be reduced if necessary.

In some patients octreotide may alter absorption of fats in the intestine.

Decreased cobalamin (vitamin B12) and abnormal cobalamin absorption test values (Schilling test) have been noted with Octreotide. When using octreotide in patients with a history of vitamin B12 deficiency, it is recommended that cobalamin levels be monitored.

Management recommendations for patients during treatment with Octreotide regarding gallstone formation:

– Patients should have an initial gallbladder ultrasound before prescribing Octreotide;

– Repeated gallbladder ultrasounds should be performed during treatment with Octreotide, preferably at 6-12 month intervals;

If gallstones are detected before treatment begins, the potential benefits of Octreotide therapy should be evaluated against the possible risks associated with their presence. There is no evidence of any adverse effect of octreotide on the course or prognosis of pre-existing gallstone disease.

Management of patients in whom gallstones form during treatment with Octreotide:

– asymptomatic gallstones. Use of Octreotide can be discontinued or continued – according to a benefit/risk assessment. In either case, there is no need to do anything other than continue monitoring, making it more frequent if necessary;

– gallstones with clinical symptoms. The use of octreotide can be discontinued or continued – according to a benefit/risk assessment. In either case the patient should be treated as in other cases of gallstones with clinical manifestations. Medical treatment includes the use of combinations of bile acids (for example, chenodeoxycholic acid at a dose of 7.5 mg/kg/day in combination with ursodeoxycholic acid at the same dose) with ultrasound monitoring until the stones have completely disappeared.

In treatment of endocrine tumors of the gastrointestinal tract and pancreas with Octreotide in rare cases a sudden relapse of the disease symptoms may occur. In patients with insulinomas during treatment with Octreotide there may be increased severity and duration of hypoglycemia (it is connected with more pronounced suppressive effect on growth hormone and glucagon secretion than on insulin secretion, as well as with shorter duration of inhibitory effect on insulin secretion). These patients should be closely monitored at regular intervals, both at the start of treatment with Octreotide and with each change in dose.

Significant fluctuations in blood glucose concentrations may be attempted to be reduced by administering Octreotide more frequently at lower doses. In patients with type 1 diabetes, octreotide may reduce the need for insulin. In nondiabetic and type 2 diabetic patients with partially preserved insulin secretion, administration of octreotide may result in postprandial hyperglycemia. When using Octreotide in patients with diabetes mellitus, blood glucose concentration control and antidiabetic therapy are recommended.

Because there is an increased risk of developing type 1 diabetes after bleeding from esophageal and gastric varices, and patients with diabetes may also have changes in insulin requirements, systematic monitoring of blood glucose concentrations is necessary in these cases.

The dosing regimen of concomitantly used diuretics, beta-adrenoblockers, BKK, insulin, oral hypoglycemic agents, and glucagon must be corrected.

The effect on the ability to drive vehicles and operate machinery. Some side effects of Octreotide may adversely affect the ability to drive vehicles and other mechanisms requiring increased concentration, accuracy and speed of psychomotor reactions. In this regard, it is recommended to exercise caution when driving vehicles or operating machinery requiring increased concentration in case of the appearance of the corresponding symptoms.

Contraindications

Hypersensitivity to octreotide or other components of the drug; children under 18 years of age.

With caution: cholelithiasis (gallstone disease); diabetes mellitus.

Side effects

The digestive system: very often – diarrhea, abdominal pain, nausea, constipation, bloating; often – dyspeptic disorders, vomiting, feeling of a full/heavy stomach, steatorrhea, soft stool consistency, changes in stool color, anorexia.

Nervous system disorders: very often – headache; often – dizziness.

Endocrine system: very common – hyperglycemia; common – hypothyroidism/disorders of thyroid function (decreased levels of TSH, total and free thyroxine); hypoglycemia, impaired glucose tolerance.

Hepatobiliary system disorders: very common – cholelithiasis, i.e., gallstones formation; common – cholecystitis, disorders of colloidal stability of bile (formation of cholesterol microcrystals), hyperbilirubinemia, increased activity of liver transaminases.

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

Respiratory system: often – shortness of breath.

System: often – bradycardia; infrequent – tachycardia.

General disorders and reactions at the injection site: very often – pain at the injection site; infrequently – dehydration.

The following adverse events have been noted in clinical practice during therapy with Octreotide regardless of any causal relationship to the use of the drug.

Immune system disorders: anaphylactic reactions, allergic reactions/hypersensitivity.

Dermatological reactions: urticaria.

Hepatobiliary system disorders: acute pancreatitis, acute hepatitis without signs of cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, increased levels of ALP, GGT.

Systemic reactions: arrhythmia.

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