Sandostatin - instructions for use, dose, side effects, contraindications

The active substance of the drug Sandostatin®, octreotide, is a synthetic octapeptide, a derivative of the natural somatostatin hormone with similar pharmacological effects, but a significantly longer duration of action. Octreotide suppresses the secretion of growth hormone (GH), both pathologically elevated, and caused by arginine, exercise and insulin hypoglycemia. Octreotide Suppress also the secretion of insulin, glucagon, gastritis, serotonin, both pathologically elevated, and caused by food intake; also inhibits the secretion of insulin and glucagon, stimulated by arginine. Octreotide suppresses the secretion of thyrotropin, caused by thyroidiberin.

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

In patients with acromegaly octreotide reduces the concentration of GH and insulin-like growth factor (IGF-1) in blood plasma.Reducing the concentration of GH by 50% or more is observed in 90% of patients, with a GH concentration of less than 5 mg / ml achieved in about half of patients. In most patients with acromegaly, Sandostatin® reduces the severity of headache, soft tissue swelling, hyperhidrosis, joint pain and paresthesias. In patients with pituitary adenoma of large sizes, treatment with the drug may lead to some reduction in tumor size.

When 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 5-fluorouracil), the use of Sandostatin® can lead to an improvement in the course of the disease. Thus, when carcinoid tumors the use of the drug Sandostatin® can lead to a decrease in the expression of the "tides" of blood to the face, diarrhea, which in many cases is accompanied by a decrease in serotonin concentration in the blood plasma and excretion of 5-hydroxyindoleacetic acid by the kidneys.

When tumors characterized by hyperproduction of the vasoactive intestinal peptide (ViPoma), the use of the drug Sandostatin® leads in most patients to a decrease in secretory diarrhea of a severe degree, and, accordingly, to an improvement in the quality of life. At the same time, there is a decrease in associated electrolyte imbalance, for example, hypokalemia, which allows to cancel enteral and parenteral administration of fluid and electrolytes. Some patients slow or stop the progression of the tumor, there is a decrease in its size, as well as the size of metastases in the liver. Clinical improvement is usually accompanied by a decrease in the concentration of vasoactive intestinal peptide (VIP) in the blood plasma or by normalization.

When glucagonomes the use of Sandostatin® leads to a decrease in migrating erythema. The drug Sandostatin® does not have any significant effect on the severity of hyperglycemia in diabetes mellitus, while the need for insulin or hypoglycemic drugs for oral administration usually remains unchanged.The drug causes a decrease in the severity of diarrhea, which is accompanied by an increase in body weight. Although a decrease in the concentration of glucagon in the blood plasma under the influence of the drug Sandostatin® is transient, the clinical improvement remains stable throughout the period of application of the drug.

In patients with gastrinomas / Zollinger-Ellison syndrome when using Sandostatin® in 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 hot flashes.

In patients with insulinomas the drug Sandostatin® reduces the concentration of immunoreactive insulin in the blood (this effect can be short-term - about 2 hours). In patients with operable tumors, the drug Sandostatin® can provide restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, glycemic control can be improved without a simultaneous prolonged decrease in insulin concentration in the blood.

In patients with rare tumors, hyper-producing growth hormone releasing factor (somatoliberinomas), the drug Sandostatin® reduces the severity of the 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.

When refractory diarrhea in patients with acquired immunodeficiency syndrome (AIDS) the use of Sandostatin® results in complete or partial normalization of the stool in approximately 1/3 of patients with diarrhea not controlled by adequate antimicrobial and / or anti-

Have patients with an impending surgery on the pancreas, The use of Sandostatin® during and after surgery reduces the incidence of typical postoperative complications (eg pancreatic fistula, abscesses, sepsis, postoperative acute pancreatitis).

When bleeding from varicose veins of the esophagus and stomach in patients with cirrhosis of the liver the use of Sandostatin® in combination with specific treatment (eg, sclerosing therapy) leads to more effective stopping of bleeding and earlyrepeated bleeding, reduced transfusion volume, and improved 5-day survival. It is believed that the mechanism of action of octreotide is associated with a decrease in organ blood flow by suppressing such vasoactive hormones as VIP and glucagon.

Pharmacokinetics:

Suction

After a subcutaneous (sc) injection of Sandostatin® octreotide quickly and completely absorbed. The maximum concentration of octreotide in the blood plasma is observed after 30 minutes.

Distribution

Communication with plasma proteins is 65%. The binding of octreotide to the formed elements of the blood is extremely insignificant. The volume of distribution is 0.27 l / kg.

Excretion

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

Indications:

Acromegaly. To control the main manifestations of the disease and reduce the concentration of GH and IGF-1 in blood plasma in the absence of sufficient effect from surgical treatment or radiation therapy,and also treatment of patients with acromegaly in the presence of contraindications to surgical treatment, or in case of refusal from such; treatment in the period after radiotherapy until the development of its full effect.

Secreting endocrine tumors of the gastrointestinal tract and pancreas - for symptom control:

- carcinoid tumors with carcinoid syndrome;

- VIPoms;

- glucagonomes;

- gastrinomas / Zollinger-Ellison syndrome - as a rule, and combinations with proton pump inhibitors and H blockers₂-gistaminovyh receptors;

- insulinoma (for the control of hypoglycemia in the preoperative period, as well as for maintenance therapy).

Somatoliberinoma (tumors characterized by hyperproduction of the releasing factor GR).

The drug Sandostatin® is not an antitumor drug and its use can not lead to the cure of this category of patients.

Control of symptoms refractory diarrhea associated with AIDS.

Prevention complications after operations on the pancreas.

Stop bleeding and prevention of bleeding recurrence from varicose veins of the esophagus and stomach in patients with cirrhosis in combination with specific therapeutic measures, for example, endoscopic sclerosing terapi.

Contraindications:

Hypersensitivity to octreotide or other components of the drug.

Carefully:

With cholelithiasis, diabetes mellitus; with simultaneous application with drugs with a narrow therapeutic index, the metabolism of which is carried out with the participation of isoenzyme CYP3A4 (e.g., quinidine, terfenadine).

Pregnancy and lactation:

The use of octreotide in pregnancy has not been studied. There is limited experience with the drug in pregnant women with acromegaly in clinical practice (in half the cases, the outcome of pregnancy is unknown). Most of the pregnant women received octreotide therapy in the first trimester of pregnancy (as a drug Sandostatin® 100-300 μg / day PO or Sandostatin® LAR 20-30 mg per month). Approximately 70% of cases with a known outcome of the patient independently decided to continue therapy with the drug during pregnancy. In most patients (cases with a known outcome), the pregnancy ended with the birth of healthy children, but there were also reported several spontaneous abortions in the first trimester and cases of abortion.

When octreotide was used during pregnancy, there were no cases of congenital malformations in children.

Use the drug during pregnancy should only be in case of emergency.

In studies in animals, reproductive toxicity has not been identified. Some individuals of rats had a transient growth retardation, possibly a feature of the endocrine profile of the species.

It is not known whether the octreotide in human milk from humans. In studies in animals, the drug was isolated with milk. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Acromegaly

When acromegaly Initially, the drug is administered at 0.05-0.1 mg p / c at intervals of 8 or 12 hours. Further dose adjustment should be based on monthly determinations of the concentration of GH and IGF-1 in the blood (target concentration: GH <2.5 ng / ml, IGF-1 within the normal range), analysis of clinical symptoms and tolerability of the drug. In most patients, the optimal daily dose is 0.3 mg. Do not exceed the maximum dose of 1.5 mg per day.In patients receiving the drug Sandostatin® in a stable dose, the determination of the GH concentration should be carried out every 6 months. If, after three months of treatment with Sandostatin® not observed sufficient decrease in the concentration of GH and improvement of the clinical picture of the disease, therapy should be discontinued.

Endocrine tumors of the gastrointestinal tract and pancreas

When endocrine tumors of the gastrointestinal tract and pancreas, gland the drug is administered SC in the initial dose of 0.05 mg 1-2 times / day. Subsequently, depending on the clinical effect achieved, influence on the concentration of hormones produced by the tumor (in the case carcinoid tumors - influence the selection of 5-hydroxyindoleacetic acid in the urine) and tolerability, the dose can be gradually increased up to 0.1-0.2 mg of 3 times / day. In exceptional cases, higher doses may be required. The maintenance dose should be selected individually.

When carcinoid tumors if drug therapy Sandostatin® maximum tolerated dose for 1 week was not effective, the treatment should not continue.

Refractory diarrhea associated with AIDS

When refractory diarrhea associated with AIDS the drug is given SC in the initial dose of 0.1 mg 3 times / day. If after one week of treatment there is no clinical improvement, the dose of the drug should be increased individually, up to 0.25 mg 3 times / day. Correction of the dose is carried out taking into account the dynamics of stool and the tolerance of the drug. If during the week of treatment with Sandostatin® at a dose of 0.25 mg 3 times a day, there is no improvement, therapy should be discontinued.

Preventive maintenance of complications after operations on a pancreas

For prevention of complications after operations on the pancreas injected SC at a dose of 0.1 mg 3 times / day for 7 consecutive days, starting from the day of surgery (at least 1 hour before laparotomy).

Bleeding from varicose veins of the esophagus and stomach

When bleeding from varicose veins of the esophagus and stomach the drug is administered at a dose of 25 μg / h by continuous intravenous infusion for 5 days. The drug Sandostatin ® can be diluted with an isotonic solution of sodium chloride. In patients with cirrhosis of the liver with bleeding from varicose veins of the esophagus, there was a good tolerability of drug therapy, within 5 days to 50 mcg / h in the form of continuous intravenous infusion.

Use in selected patient groups

Patients aged> 65 years

At present, there is no evidence of a decrease in the tolerability of drug therapy in elderly people and the need for correction of the dosing regimen.

Use in children

The experience with Sandostatin® in children is very limited.

Patients with impaired hepatic function

Since there are data on the increase in the half-life of octreotide in patients with cirrhosis of the liver, correction of the maintenance dose in patients with impaired liver function is recommended.

Patients with impaired renal function

In patients with impaired renal function, dosage adjustment is not required.

Instructions for use

The preparation in its original packaging, intended for use in the near future, can be stored at a temperature of no higher than 25 ° C for not more than 2 weeks.

Subcutaneous administration

Before self-administration of s / s injections of Sandostatin® to a doctor or nurse, the patient should be taught the correct technique for performing this manipulation.

In order to reduce the unpleasant sensations before the injection, it is necessary to keep the drug until it reaches room temperature.Do not administer the drug in the same place with short periods of time. Ampoules should be opened immediately before the administration of the drug; Unused solution should be disposed of.

Intravenous administration

Before parenteral administration, the solution should be visually assessed for changes in color or presence of mechanical inclusions.

The drug Sandostatin® (octreotide acetate) for 24 hours retains physical and chemical stability in a sterile 0.9% solution of sodium chloride or 5% aqueous glucose solution. However, due to the fact that the drug Sandostatin® can influence glucose metabolism, it is preferable to use physiological saline. The prepared solution retains its physical and chemical stability at a temperature below 25 ° C for at least 24 hours. To avoid microbial contamination, the solution is preferably used immediately after preparation. If the solution is not used immediately after preparation, it should be stored at a temperature of 2 to 8 ° C not more than 24 hours. Before use, the solution should be kept at room temperature.

The total time between dilution, storage in the refrigerator and the end of the administration of the solution should not exceed 24 hours.

If necessary, / in the administration of Sandostatin®, the contents of one ampoule containing 0.5 mg of active substance should be diluted in 60 ml of 0.9% sodium chloride solution; the prepared solution should be injected / dripped. Infusion is repeated at the required frequency in accordance with the recommended duration of treatment. Perhaps in / in the introduction of the drug solution and in a lower concentration.

Side effects:

The main undesirable phenomena (AEs) observed with the use of octreotide were disorders of the gastrointestinal tract and nervous system, violations of the liver and bile ducts, as well as disorders of metabolism and nutrition.

In clinical studies, diarrhea, abdominal pain, nausea, bloating, headache, cholelithiasis, hyperglycemia and constipation were most frequently observed with the use of the drug. Also, dizziness, pain of different localization, violation of colloidal bile stability (formation of microcrystals of cholesterol),thyroid dysfunction (decrease in thyroid-stimulating hormone concentration, total and free thyroxin), mild consistency of the stool, decreased tolerance to glucose, vomiting, asthenia and hypoglycemia.

When applying the drug in rare cases, there may be phenomena reminiscent of acute intestinal obstruction: progressive bloating, severe pain in the epigastric region, abdominal wall tension and muscular dysfunction.

Despite the fact that excretion of fats with feces may increase, there is no evidence that prolonged treatment with octreotide can lead to the development of nutritional deficiencies due to malabsorption (malabsorption). The likelihood of such side effects can be reduced by administering the drug between meals or at bedtime.

There were reported very rare cases of acute pancreatitis in the first hours or days after the administration of the drug Sandostatin®, which was resolved on its own after the drug was discontinued. In addition, with prolonged use of the drug Sandostatin®, there were cases of development of pancreatitis caused by 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 segment changes ST and T wave. Since there were concomitant heart diseases in this category of patients, a causal relationship between the use of octreotide and the development of these undesirable phenomena has not been established.

AEs are grouped according to the classification of organs and systems of organs of MedDRA, listed in order of decreasing frequency of occurrence.

The following criteria were used to determine the incidence of adverse events identified in clinical trials: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000), including individual messages.

Disorders from the gastrointestinal tract: very often - diarrhea, abdominal pain, nausea, constipation, bloating; often - indigestion, vomiting, feeling of filling / gravity in the abdomen, steatorrhea, soft consistency of the stool, discoloration of the stool.

Disturbances from the nervous system: very often - headache; often - dizziness.

Disorders from the endocrine system: often - hypothyroidism, thyroid dysfunction (decrease in thyroid-stimulating hormone, total and free thyroxine).

Disorders from the metabolism and nutrition: very often hyperglycemia: often - hypoglycemia, impaired glucose tolerance, decreased appetite; infrequently - dehydration.

Disturbances from the liver and bile ducts: very often - cholelithiasis; often - cholecystitis, violation of the colloidal stability of bile (formation of microcrystals of cholesterol), hyperbilirubinemia.

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

Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath.

Heart Disease: often bradycardia; infrequently - a tachycardia.

General disorders and disorders at the site of administration: very often - reactions at the injection site; often - asthenia.

Laboratory and instrumental data: often - increased activity "hepatic" transaminases.

Adverse events, identified in the postmarketing period on the basis of individual spontaneous reports and cases, described in the literature (the frequency is unknown)

Since data on undesirable phenomena in the postmarketing period were obtained on the basis of voluntary spontaneous messages from a population of unknown numbers, it is impossible to estimate the frequency of their occurrence (the frequency is unknown). Undesirable phenomena are classified according to the systems of organs, within each system of organs, undesirable phenomena are arranged in order of decreasing importance.

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

Disturbances from the skin and subcutaneous tissues: hives.

Disorders from the liver and bile ducts: acute pancreatitis, acute hepatitis without the phenomena of cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice.

Laboratory and instrumental data: increased activity of alkaline phosphatase and gamma-glutamyl transferase.

Heart Disease: arrhythmias.

Overdose:

Individual cases of overdose with Sandostatin® in children and adults have been reported in clinical practice. In case of accidental use of the drug in adults at a dose of 2400-6000 μg / day IV infusion (infusion rate 100-250 μg / hour) or SC (1500 μg 3 times a day), there was an arrhythmia, a decrease in blood pressure,sudden cardiac arrest, hypoxia of the brain, pancreatitis, steatosis of the liver, diarrhea, weakness, inhibition, weight loss, hepatomegaly and lactic acidosis. In case of accidental use of Sandostatin® in children in a dose of 50-3000 μg / day IV infusion (infusion rate of 2.1-500 μg / h) or p / k (50-100 μg) only mild hyperglycemia was noted.

With the administration of Sandostatin® at a dose of 3000-30000 μg / day (divided into several administrations), no unforeseen undesirable phenomena were detected in cancer patients (except as indicated in the "Side effect" section).

Interaction:

It may be necessary to correct the dose of beta-adrenoblockers, blockers of "slow" calcium channels, drugs to correct the water-electrolyte balance when they are used simultaneously with octreotide.

It may be necessary to adjust the dose of insulin or drugs for the treatment of diabetes when they are used together with the drug Sandostatin®.

Octreotide reduces the absorption of cyclosporine and slows the absorption of cimetidine. The simultaneous use of octreotide and bromocriptine increases the bioavailability of the latter.

There is evidence that somatostatin analogues can reduce the metabolic clearance of substances whose conversion pathway involves enzymes of the cytochrome P450 system, which may be due to the suppression of GH. Since it can not be ruled out that octreotide may also have this effect, caution should be exercised when using drugs metabolized by isoenzyme CYP3A4 and having a narrow range of therapeutic concentrations (eg, quinidine, terfenadine).

Special instructions:

General recommendations

For tumors of the pituitary gland secreting GH, careful monitoring of patients receiving the drug Sandostatin® is necessary, since it is possible to increase the size of the tumor with the development of such a serious complication as narrowing of the visual fields. In these cases, consideration should be given to the need for other treatments. Since reducing the concentration of GH and normalizing the concentration of IGF-1 against the background of therapy with octreotide can lead to the restoration of fertility in women with acromegaly, when using the drug for patients of childbearing age, reliable methods of contraception should be used.

When using the drug Sandostatin® for a long period of time, it is necessary to monitor the function of the thyroid gland.

Disorders from the cardiovascular system

When the drug was used, there were cases of bradycardia (gradation "often"). There may be a need to reduce the dose of run-adrenoblockers, blockers of "slow" calcium channels or drugs that affect the water-electrolyte balance.

Disturbance of nutrition

In some patients octreotide can change the absorption of fats in the intestine.

Against the background of the use of octreotide, there was a decrease in the concentration of vitamin B₁₂ and the deviation of the indices of the cobalamin absorption test (Schilling test) from the norm.

When using Sandostatin® in patients with vitamin B deficiency₁₂ in the anamnesis it is recommended to control its concentration.

Disturbances from the liver and bile ducts

All patients should undergo ultrasound examination of the gallbladder before treatment, and also every 6-12 months of Sandostatin®. In the presence of gallstones before the start of therapy with the drug,The possibility of therapy should be assessed individually based on the possible risk to potential benefit of drug therapy. There is no evidence of worsening of the course of the existing cholelithiasis with Sandostatin®.

Recommendations for the formation of gallstones in the application of the drug Sandostatin®

a) Asymptomatic stones of the gallbladder

Continuation of drug therapy with a reassessment of the benefit / risk ratio. No treatment is required; follow-up is recommended.

b) Stones of the gallbladder with clinical symptoms

Depending on the benefit / risk ratio, discontinue or continue therapy with the drug. Treatment of a patient with gall bladder stones, accompanied by clinical symptoms, must meet the accepted standards of therapy. Drug treatment includes the use of combinations of bile acid preparations (for example, chenodeoxycholic acid in combination with ursodeoxycholic acid in appropriate doses) with ultrasound control until the stones disappear completely.

Endocrine tumors of the gastrointestinal tract

In rare cases, patients with endocrine tumors of the gastrointestinal tract may suddenly stop effective control of symptoms in the treatment with the drug Sandostatin® with the rapid occurrence of relapse and the development of severe symptoms.

Metabolism of glucose

In connection with the inhibitory effect of the drug on GH, glucagon and insulin, the development of glucose metabolism disorders in the form of postprandial impairment of glucose tolerance, and in some cases, the development of persistent hyperglycemia as a result of prolonged use of the drug, is possible. There have also been cases of development of hypoglycemia.

In patients with insulinomas, treatment with octreotide may show an increase in the severity and duration of hypoglycemia (this is due to a more pronounced inhibitory effect on the secretion of GR and glucagon than on insulin secretion, as well as a shorter duration of inhibitory effect on insulin secretion). Care should be taken to monitor such patients at the beginning of the treatment and at each dose change. Significant fluctuations in the concentration of glucose in the blood can be prevented by more frequent administration of the drug in smaller doses.In patients with type 1 diabetes mellitus, the use of the drug may reduce the need for insulin. In patients without diabetes mellitus and type 2 diabetes mellitus with partially preserved insulin secretion, the use of Sandostatin® can lead to prandial hyperglycemia. When using Sandostatin ® in patients with diabetes mellitus, it is recommended to monitor blood glucose concentration and adjust therapy with hypoglycemic drugs.

Varicose veins of the esophagus

Since after the bleeding from the varicose veins of the esophagus and stomach increased the risk of developing type 1 diabetes, and in patients with an existing type 1 diabetes it is possible to change the need for insulin, in these cases a regular control of the concentration of glucose in the blood is necessary.

It is necessary to correct the dosage regimen of concomitantly used diuretics, beta-blockers, slow calcium channel blockers, insulin, hypoglycemic agents for oral administration, glucagon.

Impact on fertility

It is not known whether octreotide on fertility in humans.In studies in animals, no negative effect on the fertility of male and female rats with octreotide at a dose of 1 mg / kg body weight per day was found.

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

There is no evidence of the effect of Sandostatin® on the ability to drive vehicles and mechanisms.

Form release / dosage:

Solution for intravenous and subcutaneous administration, 0.05 mg / ml, 0.1 mg / ml and 0.5 mg / ml.

Packaging:

1 ml of solution in an ampoule.

5 ampoules together with instructions for use in a cardboard pack.

Storage conditions:

Store in refrigerator at 2-8 ° C.

Protect from light.

Keep out of the reach of children.

Keep in original packaging.

He freeze.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N016249 / 01

Date of registration:17.03.2010

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS CONSUMER HELS S.A. (part of Novartis groups) NOVARTIS CONSUMER HELS S.A. (part of Novartis groups) Switzerland

Information update date: & nbsp15.08.2015

Illustrated instructions

Instructions

Sandostatin® (Sandostatin®)