Indications for use
Acromegaly (if surgical treatment, radiation therapy or treatment with dopamine agonists is ineffective or impossible); endocrine tumors of the gastroenteropancreatic system (relief of symptoms of carcinoid tumors with signs of carcinoid syndrome, tumors characterized by overproduction of vasoactive intestinal peptide); glucagonomas; gastrinomas (Zollinger-Ellison syndrome), insulinomas, VIPomas; tumors characterized by hyperproduction of somatoliberin; refractory diarrhea in patients with AIDS; operations on the pancreas (prevention of complications); bleeding (including prevention of relapses) with varicose veins of the esophagus and stomach in patients with cirrhosis of the liver (emergency treatment).
Sandostatin
A synthetic derivative of the hormone somatostatin, which has similar pharmacological effects and a significantly longer duration of action. Reduces the secretion of growth hormone, TSH, has an antithyroid, antispasmodic effect. Reduces acid production and gastrointestinal motility. Suppresses pathologically increased secretion of growth hormone, peptides and serotonin produced in the gastroenteropancreatic endocrine system.
Normally, it reduces the secretion of growth hormone caused by arginine, stress and insulin hypoglycemia; secretion of insulin, glucagon, gastrin and other peptides of the gastroenteropancreatic endocrine system caused by food intake, as well as secretion of insulin and glucagon stimulated by arginine; secretion of thyrotropin caused by thyrotropin-releasing hormone.
Suppression of growth hormone secretion by octreotide (as opposed to somatostatin) occurs to a much greater extent than by insulin. The administration of octreotide is not accompanied by the phenomenon of hypersecretion of hormones through the “negative feedback” mechanism. In patients with acromegaly, it reduces the concentration of growth hormone and/or somatomedin A in plasma. A clinically significant decrease in the concentration of growth hormone (by 50% or more) is observed in almost all patients, while normalization of the content of growth hormone in plasma (less than 5 ng/ml) is achieved in approximately half of the patients.
For carcinoid tumors, the administration of octreotide can lead to a decrease in the severity of symptoms of the disease, primarily such as flushing of the face and diarrhea; clinical improvement is accompanied by a decrease in the concentration of serotonin in plasma and the excretion of 5-hydroxyindoleacetic acid in the urine.
For tumors characterized by overproduction of vasoactive intestinal peptide (VIP), a decrease in severe secretory diarrhea, which is characteristic of this condition, which in turn leads to an improvement in the patient’s quality of life. At the same time, there is a decrease in concomitant electrolyte imbalances, such as hypokalemia, which makes it possible to cancel enteral and parenteral administration of fluids and electrolytes. It is possible to slow down or stop the progression of the tumor and even reduce its size and especially liver metastases. Clinical improvement is usually accompanied by a decrease (down to normal values) in plasma VIP concentrations.
In glucagonomas, despite a marked reduction in the necrotizing migratory rash, it does not have any significant effect on the severity of diabetes mellitus (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, it causes a decrease in it, which is accompanied by an increase in body weight; there is often a rapid decrease in the concentration of glucagon in plasma, but with long-term treatment this effect does not persist. At the same time, symptomatic improvement remains stable for a long time.
In gastrinomas (Zollinger-Ellison syndrome), octreotide, used as monotherapy or in combination with H2 receptor blockers and proton pump inhibitors, can reduce the formation of HCl in the stomach, possibly reducing the severity and other symptoms, probably associated with the synthesis of peptides by the tumor, incl. "tides". In some cases, there is a decrease in plasma gastrin concentration.
In patients with insulinomas, it reduces the concentration of immunoreactive insulin in the blood (this effect, however, can be short-term - about 2 hours).
In patients with operable tumors, it can ensure the restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, normoglycemia can be achieved without a simultaneous prolonged decrease in insulin in the blood.
In patients with rare tumors that overproduce growth hormone releasing factor (somatoliberinomas), it reduces the severity of symptoms of acromegaly. This appears to be due to suppression of the secretion of growth hormone releasing factor and growth hormone itself. In the future, it is possible to reduce the size of the pituitary gland, which was enlarged before treatment.
In patients with acromegaly, administration of octreotide provides, in the vast majority of cases, a persistent decrease in growth hormone and normalization of the concentration of insulin-like growth factor 1/somatomedin C (IGF1). Significantly reduces the severity of symptoms such as headache, increased sweating, paresthesia, fatigue, pain in bones and joints, peripheral neuropathy. In patients with pituitary adenomas that secrete growth hormone, a reduction in tumor size is possible.
Sandostatin is a long-acting dosage form of octreotide intended for administration at 4-week intervals to maintain stable therapeutic octreotide serum concentrations. The microspheres include a polymer matrix that serves as a carrier of the active substance. After intramuscular administration, as a result of the destruction of microspheres in muscle tissue, a long-term and gradual release of the active substance occurs.
Directions for use and doses
- For acromegaly, the drug is initially administered at 50-100 mcg subcutaneously 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 normal values), analysis of clinical symptoms and drug tolerability. For most patients, the optimal daily dose is 300 mcg. The maximum dose of 1.5 mg/day should not be exceeded. In patients receiving Sandostatin at a stable dose, GH concentrations should be determined every 6 months. If after 3 months of treatment with Sandostatin there is no sufficient reduction in growth hormone levels and improvement in the clinical picture of the disease, therapy should be discontinued.
- For endocrine tumors of the gastrointestinal tract and pancreas, the drug is administered subcutaneously at an initial dose of 50 mcg 1-2 times a day. In the future, depending on the achieved clinical effect, 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 100-200 mcg 3 times a day. In exceptional cases, higher doses may be required. Maintenance doses of the drug should be selected individually.
- For carcinoid tumors, if treatment with Sandostatin at the maximum tolerated dose for 1 week was not effective, treatment should not be continued.
- For refractory diarrhea in AIDS patients, the drug is administered subcutaneously at an initial dose of 100 mcg 3 times a day. If after 1 week of treatment diarrhea does not subside, the dose of the drug should be increased individually, up to 250 mcg 3 times a day. Dose adjustment is carried out taking into account the dynamics of stool and tolerability of the drug. If no improvement occurs within a week of treatment with Sandostatin at a dose of 250 mcg 3 times/day, therapy should be discontinued.
- To prevent complications after pancreatic surgery, 100 mcg is administered subcutaneously 3 times a day for 7 consecutive days, starting from the day of surgery (at least 1 hour before laparotomy).
- For bleeding from varicose veins of the esophagus and stomach, the drug is administered at a dose of 25 mcg/hour by continuous intravenous infusion for 5 days. Sandostatin can be diluted with isotonic sodium chloride solution. In patients with cirrhosis of the liver with bleeding from esophageal varices, Sandostatin was well tolerated when administered for 5 days at a dose of 50 mcg/h as a continuous IV infusion.
- Currently, there is no data to suggest that elderly patients have reduced tolerability of Sandostatin and require a change in dosage regimen.
- Experience with Sandostatin in children is very limited.
- In patients with impaired liver function, adjustment of the maintenance dose is recommended, since there is evidence of an increase in T1/2 of octreotide in patients with liver cirrhosis.
- In patients with impaired renal function, no adjustment of the Sandostatin dosage regimen is required.
Overdose of the drug Sandostatin, symptoms and treatment
The number of cases of Sandostatin overdose in adults and children is limited. In adults, doses ranged from 2400–6000 mcg/day when administered by continuous infusion (100–250 mcg/hour) or subcutaneously (1500 mcg three times daily). The following adverse events have been reported: arrhythmia, hypotension, cardiac arrest, cerebral hypoxia, pancreatitis, hepatic steatosis, diarrhea, weakness, drowsiness, weight loss, hepatomegaly and lactic acidosis. In children, doses ranged from 50–3000 mcg/day and were administered by continuous infusion (2.1–500 mcg/h) or subcutaneously (50–100 mcg). The only adverse event was mild hyperglycemia. No side effects were observed in cancer patients receiving Sandostatin doses of 3000–30,000 mcg/day in separate subcutaneous doses.
special instructions
Significant fluctuations in blood glucose concentrations can be reduced by administering smaller doses more frequently; It should be borne in mind that when treating gastroenteropancreatic endocrine tumors, a sudden relapse of symptoms cannot be excluded, and in patients with insulinomas, an increase in the severity and duration of hypoglycemia. Systematic monitoring of glucose concentration is necessary, especially in patients with bleeding from esophageal varices with cirrhosis of the liver, because the risk of developing type 1 diabetes mellitus (insulin-dependent) increases; the need for insulin changes if you already have diabetes.
Pharmacokinetics
Suction
After subcutaneous administration, Sandostatin is quickly and completely absorbed. Cmax of octreotide in plasma is achieved within 30 minutes.
Distribution
Plasma protein binding is 65%. The binding of Sandostatin to blood cells is extremely insignificant. Vd is 0.27 l/kg.
Removal
T1/2 after subcutaneous injection of the drug is 100 minutes. After intravenous administration, the drug is eliminated in 2 phases, with T1/2 of 10 and 90 minutes, respectively. Most of the drug is excreted in feces, about 32% is excreted unchanged in urine. The total clearance is 160 ml/min.
Side effect
The main adverse events observed with the use of Sandostatin were reactions at the injection site of the drug and reactions from the gastrointestinal tract.
The most common symptoms observed when using Sandostatin were diarrhea, abdominal pain, flatulence, pain or irritation at the injection site.
Transient gastrointestinal disturbances were observed in 10% of patients and usually resolved with continued drug therapy.
Determination of the frequency of adverse reactions: very often (≥1/10), often (≥1/100, ≤1/10), sometimes (≥1/1000, ≤1/100), rarely (≥1/10,000, ≤ 1/1000), very rare (≤ 1/10,000), including isolated reports.
From the digestive system: often - diarrhea, cramping abdominal pain, constipation, flatulence; sometimes - cholecystitis; rarely - steatorrhea, nausea, vomiting, bloating, formation of gallstones; very rarely - acute pancreatitis, anorexia, loose stools, acute hepatitis without cholestasis, hyperbilirubinemia, increased levels of alkaline phosphatase, GGT and liver transaminase activity.
Dermatological reactions: sometimes - temporary hair loss.
From the cardiovascular system: sometimes - bradycardia, tachycardia.
Allergic reactions: rarely - hypersensitivity, rash; very rarely - anaphylaxis.
From the endocrine system: very rarely - hypoglycemia, hyperglycemia.
From the respiratory system: very rarely - shortness of breath.
Local reactions: pain, itching or burning sensation, redness and swelling at the site of subcutaneous injection (usually disappear within 15 minutes). The severity of local reactions can be reduced if you use a solution at room temperature, or if you introduce a smaller one; volume of a more concentrated solution.
Others
Although the excretion of fat in the feces may be increased, there is no evidence to date that long-term treatment with octreotide can lead to the development of nutritional deficiencies due to malabsorption (malabsorption).
The incidence of side effects from the gastrointestinal tract can be reduced by increasing the time intervals between meals and the administration of Sandostatin.
Very rare cases of acute pancreatitis have been reported that developed in the first hours or days of subcutaneous use of Sandostatin and disappeared after discontinuation of the drug. In addition, with long-term use of Sandostatin subcutaneously, cases of pancreatitis associated with cholelithiasis have been reported.
When using Sandostatin, dysfunction of the thyroid gland (both decreased and increased activity) and dyspeptic symptoms were rarely observed.
Cases of arrhythmias have been reported in patients treated with octreotide acetate.
According to an ECG study, during the use of the drug, the following were observed: prolongation of the OT interval, deviation of the electrical axis of the heart, early repolarization, low-voltage ECG type, displacement of the transition zone, early P wave and nonspecific changes in the ST segment and T wave. Since many patients with acromegaly and carcinoid tumors are associated with heart disease; a cause-and-effect relationship between the use of Sandostatin and the development of these adverse events has not been established.
Drug interactions
Sandostatin reduces the absorption of cyclosporine and slows down the absorption of cimetidine.
The combined use of octreotide and bromocriptine increases the bioavailability of bromocriptine.
There is evidence that somatostatin analogues may reduce the metabolic clearance of substances metabolized by isoenzymes of the cytochrome P450 system, which may be due to GR suppression. Since it cannot be excluded that octreotide may also have this effect, caution should be exercised when prescribing drugs that are metabolized by the CYP3A4 isoenzyme and have a narrow therapeutic concentration range (for example, quinidine, terfenadine).
Overdose
Doses of octreotide up to 2000 mcg in the form of subcutaneous injections 3 times a day for several months were well tolerated.
Symptoms: the maximum single dose for intravenous bolus administration to an adult patient was 1 mg, with a decrease in heart rate, flushing, cramping abdominal pain, diarrhea, a feeling of emptiness in the stomach and nausea; all these symptoms resolved within 24 hours of drug administration.
One patient was mistakenly given an excessive dose of Sandostatin via long-term infusion (250 mcg/h for 48 hours instead of 25 mcg/h), which was not accompanied by side effects.
No life-threatening reactions were observed in acute overdose.
Treatment: symptomatic therapy.
