Genfastat - instructions for use, doses, side effects, contraindications

Excipients: glacial acetic acid 2.0 mg, sodium acetate trihydrate 2.0 mg, sodium chloride 7.0 mg, phenol (only at a dose of 200 μg) 5.0 mg, water for injection 1 ml.

Description:

Transparent colorless liquid.

Pharmacotherapeutic group:Somatostatin analogue synthetic

ATX: & nbsp

H.01.C.B.02 Octreotide

Pharmacodynamics:

Octreotide is a synthetic octapeptide, which is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a much longer duration of action.

The drug suppresses the pathologically increased secretion of growth hormone (GR), as well as peptides and serotonin produced in the gastroenteropancreatic endocrine system. In healthy individuals octreotide, like somatostatin, suppresses the secretion of GH caused by arginine, exercise and insulin hypoglycemia; secretion of insulin, glucagon, gastrin and other peptides of the gastroenteropancreatic endocrine system caused by food intake, as well as the secretion of insulin and glucagon stimulated with arginine; secretion of thyrotropin, caused by thyroidiberin. In octreotide, in contrast to somatostatin, the inhibitory effect on GH secretion is expressed to a much greater extent than on the secretion of insulin. The administration of octreotide is not accompanied by the effect of hypersecretion of hormones by the mechanism of negative feedback.

In patients with acromegaly, the administration of octreotide provides, in the vast majority of cases, a persistent decreaseconcentration in the blood plasma of GH and normalization of the concentration of insulin-like growth factor 1 (IGF-1).

In most patients with acromegaly octreotide significantly reduces the severity of symptoms such as headache, increased sweating, paresthesia, a sense of fatigue, pain in the bones and joints, peripheral neuropathy. It was reported that treatment with octreotide of individual patients with adenomas of the pituitary gland secreting GH led to a decrease in the size of the tumor.

In carcinoid tumors, the use of octreotide can lead to a decrease in the severity of the symptoms of the disease, primarily such as hot flashes and diarrhea. In many cases, clinical improvement is accompanied by a decrease in the concentration of serotonin in the blood plasma and the excretion of 5-hydroxyindoleacetic acid in the urine. In tumors characterized by hyperproduction of the vasoactive intestinal peptide (WIPOM), the use of octreotide in most patients reduces the severe secretory diarrhea that is characteristic of this condition, which in turn leads to an improvement in the quality of life of the patient.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. According to computed tomography, in some patients, the progression of the tumor slows or stops, and even its size decreases; metastatic foci in the liver. Clinical improvement is usually accompanied by a decrease (up to normal values) of the concentration of vasoactive intestinal peptide (VIP) in the blood plasma.

With glucagonomes, the use of octreotide in most cases leads to a marked decrease in necrotizing migrating erythema, which is characteristic of this condition. Octreotide does not have any significant effect on the severity of diabetes mellitus, often observed in glucagonomes, and usually does not lead to a decrease in the need for insulin or oral hypoglycemic drugs. In patients with diarrhea octreotide causes it to decrease, which is accompanied by an increase in body weight. When the use of octreotide is often marked by a rapid decrease in plasma glucagon concentration, however, with prolonged treatment this effect is not preserved.At the same time, the improvement in clinical symptoms remains stable for a long time.

With gastrinomas / Zollinger-Ellison syndrome octreotide, used as a monotherapy or in combination with blockers H₂-receptors and proton pump inhibitors, can reduce the formation of hydrochloric acid in the stomach and lead to clinical improvement, incl. and in relation to diarrhea. It is also possible to reduce the severity and other symptoms likely associated with the synthesis of peptides by the tumor, incl. tides. In some cases there is a decrease in the concentration of gastrin in the blood plasma.

In patients with insulinomas octreotide reduces the concentration in the blood plasma of immunoreactive insulin. In patients with operable tumors octreotide can provide recovery and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, the control of glycemia can improve without a simultaneous prolonged decrease in the concentration of insulin in the blood plasma.

In patients with rare tumors, hyper-producing rylening factor GH (somatoliberinomas), octreotide reduces the severity of symptoms of acromegaly. This, apparently, is due to the suppression of the secretion of the releasing factor of GR and of the GH itself. In the future, it is possible to reduce the size of the pituitary gland, which were increased before the treatment.

Approximately 1/3 of patients with acquired immunodeficiency syndrome (AIDS) who suffer from refractory diarrhea, uncontrolled by adequate antimicrobial and / or antidiarrhoeic therapy, use octreotide leads to complete or partial normalization of the stool.

In patients with pancreas surgery, the use of octreotide 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 octreotide in combination with specific treatment (for example, sclerosing therapy) leads to more effective stopping of bleeding and early rebleeding, reducing the volume of transfusions and improving the 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:

After subcutaneous administration, the drug is quickly and completely absorbed. Time to reach the maximum concentration in the blood plasma (5.2 mg / ml at a dose of 0.1 mg) - 30 minutes. The connection with plasma proteins is 65%, with uniform elements of blood - very insignificant. The volume of distribution is 0.27 l / kg. The total clearance is 160 ml / min. Half-life (T_1/2) is 100 minutes. Most of the drug is excreted by the intestine, about 32% are excreted unchanged by the kidneys. After intravenous administration, excretion is carried out in 2 phases, with T_1/2-10 and 90 minutes respectively. In elderly patients, the clearance of octreotide is reduced, and T_1/2 increases. In severe chronic renal failure, the clearance decreases by a factor of 2.

Indications:

Acromegaly (when adequate control of the manifestations of the disease is due to subcutaneous administration of octreotide, in the absence of sufficient effect from surgical treatment and radiation therapy, for preparation for surgical treatment, for treatment between radiotherapy courses before the development of a persistent effect, in inoperable patients);

In the therapy of endocrine tumors of the gastrointestinal tract (GI tract) and pancreas, when the injection of the drug provides an adequate control of the manifestations of the disease:

- carcinoid tumors with the phenomena of carcinoid syndrome;

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

- VIPoms;

- gastrinomas (Zollinger-Ellison syndrome) - usually in combination with proton pump inhibitors and histamine blockers H₂-receptors;

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

Somatoliberinoma (tumors characterized by hyperproduction of the rylening factor of GR). Genfastat® is not an antitumor drug and its use can not lead to the cure of this category of patients;

Control of symptoms of refractory diarrhea in AIDS patients;

Preventive maintenance of complications after operations on a pancreas; stop bleeding and prevent bleeding from varicose veins of the esophagus with cirrhosis of the liver (in combination with endoscopic sclerosing therapy).

Contraindications:

Hypersensitivity to octreotide or other components of the drug.

Carefully:Xolelithiasis, diabetes, pregnancy and lactation.

Pregnancy and lactation:

The use of octreotide in pregnant women has not been studied. There is limited experience with the use of octreotide in clinical practice in pregnant patients with acromegaly (in half the cases, the outcome of pregnancy was not known). 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. With the use of octreotide during pregnancy to the present, there have been no cases of congenital malformations in children. Pregnant women are prescribed only in cases of extreme necessity.

In experimental studies octreotide did not exert a direct or indirect negative influence on the course of pregnancy, fetal formation and maturation, childbirth and postnatal development of animals, except for temporary growth retardation.

It is not known whether octreotide with human milk in humans, in animals there is a secretion of the drug with breast milk. If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

The drug Genfastat® is intended for subcutaneous (subcutaneous) and intravenous (IV) administration. The initial dose is 50 mcg / day p / to 1 or 2 times a day. After that, the number of injections and dosage can be gradually increased, based on the tolerability, clinical response and effects on the concentration of hormones in the blood plasma produced by the tumor (in the case of carcinoid tumors - the effect on excretion of urinary 5-hydroxyindoleacetic acid). The drug is usually used 2-3 times a day.

With acromegaly the drug is administered subcutaneously in an initial dose of 50-100 μg, at intervals of 8 or 12 hours. Subsequently, the dose selection is 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 limits of normal values), analysis of clinical symptoms and drug tolerability. In most patients, the daily dose is 200-300 μg. Do not exceed the maximum dose of 1500 μg / day.In patients receiving octreotide in a stable dose, the determination of the concentration of GH in the blood plasma should be carried out every 6 months! If after 3 months of treatment there is no sufficient decrease in the concentration of GH in the blood plasma and improve the clinical picture of the disease, therapy should be discontinued.

When enprecrinal tumors of gastroenteropancreatic system - The drug is given SC in the initial dose of 50 mcg 1-2 times a day. In the future, depending on the effect achieved, the effect on the concentration of hormones in the blood plasma produced by the tumor (in the case of carcinoid tumors - the effect on the release of 5-hydroxyindoleacetic acid in the urine) and tolerability, the dose can be gradually increased to 100-200 μg 3 times per day.

In exceptional cases, higher doses may be required. Supportive doses of the drug should be selected individually. In carcinoid tumors, if treatment with octreotide at the maximum tolerated dose for 1 week is not effective, treatment should not continue.

With refractory diarrhea in patients with AIDS the drug is given SC in the initial dose of 100 μg 3 times / day.If after one week of treatment the diarrhea does not subside, the dose of the drug should be increased individually, up to 250 mcg 3 times / day. Correction of the dose is carried out taking into account the dynamics of the frequency of stool and the tolerance of the drug. If there is no improvement during the week of treatment with octreotide at a dose of 0.25 mg 3 times a day, therapy should be discontinued.

To prevent complications after operations on the pancrease - n / k, the first dose of 100 mcg for 1 h before laparotomy, after the operation - 100 mcg 3 times a day, for 7 consecutive days. In exceptional cases, higher doses may be required. Supportive doses of the drug should be selected individually.

In the event that therapy in the maximum tolerated dose is not effective within 1 week, therapy should be discontinued.

To stop bleeding from varicose-dilated esophagus veins - in / in the drip at a rate of 25 mcg / h for 5 days.

With n / k introduction, multiple injections of the drug should be avoided in the same place for a short period of time.

With iv introduction of the drug immediately before use, the contents of the single-use vial or reusable vial should be diluted in physiological saline.The dilution volume will depend on the infusion system used, and it should be modified to ensure continuous administration of octreotide at the recommended rate. After the drug has been diluted, the resulting solution should be used within 24 hours. It is necessary to destroy the unused solution. The vial with the drug for reusable use (200 μg / ml) after the first opening should be stored in the refrigerator at a temperature of 2-8 ° C and used for 15 days. Before applying the solution, it must be checked for transparency, presence of particles, sediment, discoloration and leakage, in all cases when the solution and material of the package permit. Do not use the drug if it is cloudy, contains particles, sediment, if its color has changed or traces of streaks are visible.

Use in selected patient groups

Currently, there is no data that would indicate the need to adjust the dose of the drug in the elderly and in patients with impaired renal function.

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

The experience with octreotide in children is limited.

Side effects:

To determine the frequency of undesired reactions, the following criteria were used: very often (> 1/10); often (> 1/100, <1/10); sometimes (> 1/1000, <1/100), rarely (> 1/10000, <1/1000), very rarely (<1/10000), including individual messages.

From the digestive system: very often - diarrhea, abdominal pain, nausea, constipation, bloating; often - dyspeptic disorders, vomiting, feeling of filling / heaviness of the abdomen, steatorrhea, mild consistency of the stool, discoloration of the stool, anorexia; rarely - progressive bloating, severe pain in the epigastric region, muscle tension of the abdominal wall.

From the nervous system: very often - headache; often - dizziness.

From the endocrine system: very often hyperglycemia; often - hypothyroidism / thyroid dysfunction (reduced thyroid stimulating hormone, total and free thyroxine); hypoglycemia, impairment (decrease) of glucose tolerance.

From the hepatobiliary system: very often - cholelithiasis,te the formation of stones in the gallbladder; often - cholecystitis, violation of colloidal bile stability (formation of microcrystals of cholesterol), hyperbilirubinemia, increased activity of "liver" transaminases; very rarely - acute pancreatitis; reactive pancreatitis associated with cholelithiasis; acute hepatitis without the phenomena of cholestasis, jaundice, an increase in the plasma content of alkaline phosphatase, gamma-glutamyltransferase.

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

From the immune system: rarely anaphylactic shock, hypersensitivity reactions.

From the respiratory system: often - shortness of breath.

From the side of the cardiovascular system: often bradycardia, sometimes tachycardia; rarely - arrhythmia.

Common disorders and reactions at the site of administration: very often - pain at the injection site, often - asthenia; sometimes - dehydration.

Overdose:

Individual cases of overdose of octreotideadete and adults have been reported in clinical practice. If octreotide is used randomly in adults at a dose of 2400-6000 μg / day, injected intravenously (infusion rate 100-250 μg / hr) or subcutaneously (1500 μg 3 times a day),observed: the development of arrhythmias, lowering blood pressure, sudden cardiac arrest, brain hypoxia, pancreatitis, steatohepatosis, diarrhea, weakness, inhibition, weight loss, hepatomegaly and lactic acidosis. With occasional use of octreotide in children at a dose of 50-3000 μg / day, administered intravenously drip (infusion rate 2.1-500 μg / hr) or subcutaneously (50-100 μg), only mild hyperglycemia was noted.

When subcutaneous administration of octreotide at a dose of 3000-30000 μg / day (divided into several administrations) in patients with tumors, no new undesirable phenomena (with the exception of those indicated in the "Side effect" section) were identified.

Interaction:

Octreotide reduces the absorption of cyclosporine, slows the absorption of cimetidine.

With the simultaneous use of octreotide and bromocriptine, the bioavailability of the latter increases.

It is necessary to correct the dosage regimen of concomitantly used diuretics, beta-blockers, blockers of "slow" calcium channels, insulin, oral hypoglycemic drugs, glucagon.

There is evidence that somatostatin analogues can reduce the metabolic clearance of drugs, which occurs with the participation of P450 enzymes (may be due to GH suppression).Since it is impossible to exclude similar effects of octreotide, drugs metabolized by isoenzyme CYP3A4 and having a narrow therapeutic range of doses, should be administered with caution (for example, quinidine, terfenadine).

Special instructions:

For tumors of the pituitary gland secreting GH, careful monitoring of patients receiving octreotide, since it is possible to increase the size of tumors with the development of such serious complications as narrowing of the visual fields. In these cases, consideration should be given to the need for other treatments.

Since the decrease in the concentration in the blood plasma of the GH and the normalization of the plasma concentration of insulin-like growth factor-1 on the background of octreotide therapy can lead to the restoration of fertility in women with acromegaly, when using the drug of the patient of childbearing age, reliable methods of contraception should be used. With the appointment of octreotide for a long period of time, it is necessary to monitor the function of the thyroid gland.

In the case of bradycardia on the background of octreotide, if necessary, it is possible to reduce the dose of beta adrenoblockers,blockers of "slow" calcium channels or drugs that affect the water-electrolyte balance. In some patients octreotide can change the absorption of fats in the intestine. Against the background of octreotide, there was a decrease in the content of cyanocobalamin (vitamin AT₁₂) and deviation from the norm of the indices of cyanocobalamin absorption test (Schilling test).

When octreotide is used in patients with vitamin deficiency AT₁₂ in the anamnesis it is recommended to control the content of cyanocobalamin in the body.

In patients with type 1 diabetes mellitus octreotide can affect the exchange of glucose and, consequently, reduce the need for injected insulin. For patients with type 2 diabetes mellitus and patients without concomitant disturbance of carbohydrate metabolism, subcutaneous octreotide injections can lead to postprandial hyperglycemia. In this regard, it is recommended to regularly monitor the concentration of glucose in the blood plasma and, if necessary, correct hypoglycemic therapy.

In patients with insulinomas against the background of treatment with octreotide, there may be an increase in the severity and duration of hypoglycemia (this is associated with a more pronounced effect on the secretion of GH and glucagon,than on the secretion of insulin, as well as with a shorter duration of the inhibitory effect on the secretion of insulin). A systematic observation of these patients is shown.

Before the appointment of octreotide, patients should undergo ultrasound examination of the gallbladder (ultrasound). During treatment with octreotide, repeated ultrasound of the gallbladder should be performed, preferably at intervals of 6-12 months.

If gallbladder stones are found even before the start of treatment, it is necessary to evaluate the potential benefits of octreotide therapy in comparison with the possible risk associated with the presence of gallstones.

At the present time, there is no evidence that octreotide adversely affects the course or prognosis of an already existing cholelithiasis.

Management of patients whose gallstones are formed during treatment with octreotide

a) Asymptomatic stones of the gallbladder

The use of octreotide can be discontinued or continued - according to the benefit / risk ratio estimate. In any case, no other measures are required, except to continue inspections, making them, if necessary, more frequent.

b) Stones of the gallbladder with clinical symptoms

The use of octreotide can be discontinued or continued - according to the benefit / risk ratio estimate. In any case, the patient should be treated in the same way as in other cases of cholelithiasis with clinical manifestations. Drug treatment includes the use of combinations of bile acid preparations (for example, chenodeoxycholic acid at a dose of 7,5 mg / kg / day in combination with ursodeoxycholic acid in the same dose) under ultrasound control until the stones disappear completely.

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

There is no data on the effect of octreotide on the ability to drive a car and work with mechanisms.

Form release / dosage:Solution for intravenous and subcutaneous administration, 50 μg / ml, 100 μg / ml, 200 μg / ml and 500 μg / ml.

Packaging:

1 ml of the drug (50 μg / ml, 100 μg / ml and 500 μg / ml) or 5 ml (200 μg / ml) in a brown glass bottle capped with a rubber cap, rolled up with an aluminum cap and closed with a plastic cover to control the first opening.

5 bottles (for dosages of 50 μg / ml, 100 μg / ml and 500 μg / ml) together with instructions for use in a cardboard package.

1 bottle (for a dosage of 200 mcg / ml) together with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 8 ° C in a dark place. Do not freeze.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LS-002438

Date of registration:30.12.2011

Expiration Date:Unlimited

The owner of the registration certificate: Genfa Medica S.A. Genfa Medica S.A. Switzerland

Manufacturer: & nbsp

OMEGA LABORATORIES, Ltd. Canada

Representation: & nbspHEAD OF MEDICA SAHEAD OF MEDICA SASwitzerland

Information update date: & nbsp24.03.2017

Illustrated instructions

Instructions

Genfastat® (Genfastat®)