Instruction for use: Octreotide-Long FS

ATX Code H01CB02 Octreotide

Active substance: Octreotide

Pharmacological group

Somatostatin (synthetic analog) [Hypothalamic hormones, pituitary gland, gonadotropins and their antagonists]

Somatostatin (synthetic analog) [Antitumor hormonal agents and hormone antagonists]

Nosological classification (ICD-10)

C25 Malignant neoplasm of pancreas

VIPoma, Glucagon, Locally spread pancreatic adenocarcinoma, Inoperable pancreatic cancer, Pancreas cancer, Carcinoid pancreatic tumor, Tumors of the pancreas, Pancreatic endocrine tumors, Pancreatic exocrine tumors

C25.4 Pancreatic islet cells

Insulinoma, Carcinoma of islet cells of the pancreas, Werner-Morrison syndrome, Nezidioblastosis, Pancreatic tumors island-cell, Ostrovkovletochnye tumors of the pancreas, Pancreatic cholera

C26 Malignant neoplasm of other and inaccurately indicated digestive organs

Bowel cancer, Gastrointestinal cancer, Carcinoid GI tract, Adenocarcinoma of the intestine, Cancer of other parts of the large intestine, Argentaffinoma, Carcinoid, Enterochromaffinoma, Cancer of the colon, Colon cancer

C61 Malignant neoplasm of prostate

Adenocarcinoma of the prostate, Hormone-dependent prostate cancer, Hormone-Resistant Prostate Cancer, Malignant tumor of prostate, Malignant neoplasm of prostate, Carcinoma of the prostate, Locally-distributed non-metastatic prostate cancer, Locally advanced prostate cancer, Locally spread prostate cancer, Metastatic prostatic carcinoma, Metastatic prostate cancer, Metastatic hormone-resistant prostate cancer, Non-metastatic prostate cancer, Incompatible prostate cancer, Prostate Cancer, Prostate cancer, Common prostate cancer, Testosterone-Depot Prostate Cancer

C75.1 Malignant neoplasm of pituitary gland

Pituitary Tumor, Aumada del Castillo Syndrome, Somatoliberinoma, Pituitary adenoma, Tumors of the pituitary and suprasellar region

D01.7 In situ carcinoma of other specified digestive organs

Carcinoid pancreatic tumor, Pancreatic carcinoma

D13.7 Benign neoplasm of islet cells of the pancreas

Insuloma, Nezidioblastosis, Pancreatic tumors island-cell, Ostrovkovletochnye tumors of the pancreas

D35.2 Benign neoplasm of pituitary gland

Pituitary adenoma, Prolactinomas, Macro-prolaktinoma, Microprolactinoma, Prolactinoma, Somatoliberinoma, Aumada del Castillo Syndrome, Tumors of the pituitary and suprasellar region

D44.3 Neoplasm of uncertain or unknown pituitary nature

Macro-prolaktinoma, Microprolactinoma, Prolactinoma, Somatoliberinoma, Prolactinomas

E22.0 Acromegaly and pituitary gigantism

Pituitary gigantism, Acromegaly, Dysfunction of growth hormone secretion

E34.0 Carcinoid Syndrome

Carcinoid syndrome

K86.8.3 * Zollinger-Ellison Syndrome

Adenoma of the pancreas ulzerogennosti, gastrinoma, Zollinger-Ellison Syndrome, gastrinoma

Composition

Microspheres for the preparation of suspension for intramuscular administration of prolonged action

The composition is given below

Ingredients 1 fl.

active substance:

Octreotide acetate (in terms of octreotide), mg 10 20 30

Excipients:

DL-lactic and glycolic acid copolymer, mg 270 560 850

D-mannitol, mg 85 85 85

Carmellose sodium, mg 30 30 30

Polysorbate-80, mg 2 2 2

Description of dosage form

Active ingredient: microspheres (lyophilized powder) or compacted into a tablet porous mass of white or white with a weak yellowish tint of color.

Solvent: clear, colorless liquid.

Reduced suspension: when adding the solvent and stirring, a homogeneous suspension of white or white with a weak yellowish tint of color should form; When standing, the suspension precipitates, but it is easily resuspended by shaking; The suspension must pass into the syringe freely through needle No. 0840.

Characteristic

Octreotide-long FS is a long-acting octreotide dosage form for the / m administration, which maintains stable therapeutic octreotide concentrations in the blood for 4 weeks.

pharmachologic effect

The pharmacological action is somatostatin-like.

Pharmacodynamics

Octreotide is a synthetic octapeptide, a derivative of the natural hormone somatostatin, which has similar pharmacological effects, but with a much longer duration of action. Octreotide suppresses pathologically increased secretion of growth hormone (GH), 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. The suppressive effect on the secretion of GH in octreotide, in contrast to somatostatin, is expressed to a much greater extent than on the secretion of insulin. The introduction of octreotide is not accompanied by the phenomenon 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 decrease in the level of GH and a normalization of the concentration of insulin-like growth factor 1 (IGF-1). In patients with acromegaly, octreotide significantly reduces the severity of symptoms such as headache, increased sweating, paresthesia, fatigue, pain in the bones and joints, peripheral neuropathy. In patients with pituitary adenoma, secreting GH, leads to a decrease in the size of the tumor.

In carcinoid tumors, the use of the drug leads to a decrease in the severity of the symptoms of the disease, primarily such as blood flow to the face and diarrhea. In many cases, clinical improvement is accompanied by a decrease in serotonin concentration in plasma and excretion of 5-hydroxyindoleacetic acid in the urine.

In tumors characterized by hyperproduction of the vasoactive intestinal peptide (VIP), the use of octreotide leads to a reduction in severe secretory diarrhea characteristic of this condition, which in turn improves 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, patients are slowing or stopping the progression of tumor growth, and even a decrease in its size, especially metastases to the liver. Clinical improvement is usually accompanied by a decrease (up to normal values) of the concentration of VIP in the plasma.

With glucagonomes, the use of octreotide leads to a marked decrease in necrotizing migrating rash, which is characteristic of this condition. Octreotide does not have any significant effect on the severity of diabetes mellitus, often observed with glucagonomes, and usually does not lead to a decrease in the need for insulin or oral hypoglycemic drugs. Patients suffering from diarrhea, the drug causes a decrease in it, which is accompanied by an increase in body weight. With the use of octreotide, a rapid decrease in glucagon concentration in the plasma occurs, but with prolonged treatment this effect is not preserved. Symptomatic improvement remains stable for a long time.

In gastrinomas (Zollinger-Ellison syndrome), a drug used as a monotherapy or in combination with H2-histamine receptor blockers and proton pump inhibitors reduces the formation of hydrochloric acid in the stomach and leads to clinical improvement, incl. And in relation to diarrhea. With the introduction of octreotide, the symptoms associated with the synthesis of peptides by the tumor decrease, including. Tides of blood to the face. In some cases, a decrease in the concentration of gastrin in the plasma.

In patients with insulinomas, octreotide reduces the content of immunoreactive insulin in the blood.

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 be improved without a simultaneous prolonged decrease in the concentration of insulin in the blood.

In patients with rare tumors, hyper-releasing growth hormone releasing factor (somatoliberinomas), octreotide reduces the symptoms of acromegaly, which is associated with inhibition of growth hormone releasing hormone and GH itself. Thus, in the subsequent there is a decrease in the size of the pituitary gland, which were increased before the start of treatment.

In patients with hormone-resistant prostate cancer (PGRFA), a pool of neuroendocrine cells expressing somatostatin receptors affiliated to octreotide (SS2- and SS5-types) increases, which determines the sensitivity of the tumor to octreotide. The use of octreotide in combination with dexamethasone against the background of androgen blockade (drug or surgical castration) in patients with PGRM restores sensitivity to hormone therapy and leads to a decrease in prostate specific antigen (PSA) in more than 50% of patients. In patients with PGRD with metastases in the bone, this therapy is accompanied by a pronounced and prolonged analgesic effect, the quality of life improves.

indications

Octreotide is a pathogenetic therapy for tumors that actively express somatostatin receptors.

In the therapy of acromegaly:

When an adequate control of the manifestations of the disease is due to the sc / o administration of octreotide;

In the absence of sufficient effect from surgical treatment and radiation therapy;

To prepare 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 and pancreas:

Carcinoid tumors with the phenomena of carcinoid syndrome;

Insulinomas;

VIPoms;

Gastrinomas (Zollinger-Ellison syndrome);

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

Somatoliberynoma (tumors characterized by hyperproduction of growth hormone releasing factor).

In the treatment of hormone-resistant prostate cancer:

In the combination therapy on the background of surgical or drug castration.

Contraindications

Hypersensitivity to octreotide or other components of the drug.

With caution: cholelithiasis; diabetes.

pregnancy and lactation

Experience with the drug during pregnancy and during breastfeeding is absent, therefore this category of patients is prescribed only in case of emergency.

Use in children. There is limited experience in children.

Side effects

Criteria for assessing the incidence of adverse reactions: 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.

Local reactions: often - with a / m introduction, pain is possible, rarely - swelling and eruptions at the injection site (usually mild, short-lived).

From the digestive system: often - spastic abdominal pain, bloating, excessive gas formation, loose stools, diarrhea; Sometimes - cholecystitis; Rarely - nausea, vomiting, the formation of gallstones, steatorrhea. Although the release of fat with feces may increase, there is no indication that prolonged treatment with octreotide can lead to impaired absorption (malabsorption). Rarely, phenomena reminiscent of acute intestinal obstruction: progressive bloating, severe pain in the epigastric region, tension of the abdominal wall. There have been reports of rare cases of acute pancreatitis that developed during the first hours or days of octreotide use. With prolonged use, there have been cases of pancreatitis associated with cholelithiasis.

There are separate reports on the development of violations of liver function (acute hepatitis without cholestasis with normalization of transaminases after octreotide abolition); In t.ch. Slow development of hyperbilirubinemia, accompanied by an increase in the parameters of alkaline phosphatase, GGT.

From the endocrine system: rarely - the development of persistent hyperglycemia, hypoglycemia.

From the CCC: sometimes - bradycardia, tachycardia.

From the respiratory system: very rarely - shortness of breath.

Allergic reactions: rarely - hypersensitivity, rash; Very rarely anaphylaxis.

Other: rarely - temporary hair loss after octreotide administration.

Interaction

Octreotide reduces intestinal absorption of cyclosporine and slows the absorption of cimetidine.

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

There are published data that somatostatin analogues can reduce the metabolic clearance of substances metabolized by cytochrome P450 enzymes, which may be caused by GH suppression. Since it is impossible to exclude similar effects of octreotide, drugs metabolized by enzymes of the cytochrome P450 system and having a narrow therapeutic dosage range (eg, quinidine and terfenadine) should be administered with caution.

Dosing and Administration

In / m (deep), in the gluteus muscle. With repeated injections, the left and right sides should alternate. Suspension should be prepared immediately before injection. On the day of injection, the vial with the preparation and the ampoule with the solvent can be kept at room temperature.

In acromegaly, it is recommended that a 3-day trial be carried out with the octreotide (a solution for SC and IV administration) at a dose of 300 μg / day in order to resolve the issue of the tolerability and effectiveness of long-term treatment with Octreotide-long FS. Decreased IGF-1 level in the blood more than 60% of the initial (in the absence of signs of intolerance) will indicate a good prognosis of the drug as a prolonged primary or secondary pharmacotherapy. For patients who are less sensitive to the drug, the starting dose should be higher. For a resistant group of patients, surgical intervention is recommended. In the case of non-radical adenomectomy, a 3-day trial with a SC administration increases the sensitivity to subsequent drug therapy.

For patients in whom s / c octreotide administration provides adequate control of the manifestations of the disease, the recommended initial dose of the drug is 20 mg every 4 weeks for 3 months. You can start treatment with Octreotide-Long FS the day after the last SC administration of the octreotide solution. In the future, the dose of the drug is corrected taking into account the concentration in the serum of GH and IGF-1, as well as clinical symptoms.

If after 3 months of treatment failed to achieve an adequate clinical and biochemical effect (in particular, if the concentration of GH remains above 2.5 μg / l), the dose can be increased to 30 mg administered every 4 weeks.

In those cases where after a 3 month treatment with Octreotide-Long FS at a dose of 20 mg there is a persistent decrease in serum GH concentration below 1 μg / L, normalization of IGF-1 concentration and disappearance of reversible symptoms of acromegaly, it is possible to reduce the dose of Octreotide-Long FS up to 10 Mg. However, in these patients receiving a relatively small dose of Octreotide-Long FS, serum concentrations of GH and IGF-1, as well as the symptoms of the disease, should be carefully monitored. Patients receiving a stable dose of the drug, determination of the concentrations of GH and IGF-1 should be performed every 6 months.

With endocrine tumors of the gastrointestinal tract and pancreas for patients in whom SC administration of octreotide provides adequate control of the manifestations of the disease, the recommended initial dose of Octreotide-Long FS is 20 mg every 4 weeks. SC administration of octreotide should continue for another 2 weeks after the first administration of Octreotide-long FS. For patients who have not previously received octreotide s / c, it is recommended to start treatment with the SC administration of octreotide at a dose of 100 mcg 3 times / day for a relatively short period of time (approximately 2 weeks) in order to evaluate its effectiveness and overall tolerability. Only after this is prescribed Octreotide-long FS according to the above scheme. In the case when Octreotide-Long FS therapy for 3 months provides adequate control of clinical manifestations and biological markers of the disease, it is possible to reduce the dose of Octreotide-Long FS up to 10 mg, administered every 4 weeks. In those cases when, after 3 months of treatment with Octreotide-long FS, only partial improvement was achieved, the dose of the drug can be increased to 30 mg every 4 weeks. On the background of treatment with Octreotide-Long FS on certain days, it is possible to increase the clinical manifestations characteristic of endocrine tumors of the gastrointestinal tract and pancreas. In these cases, an additional SC administration of an octreotide solution is recommended in a dose that was used before the start of treatment with Octreotide-long FS. This may occur, mainly, in the first 2 months of treatment, until the therapeutic concentrations of octreotide in plasma are reached.

With hormone-resistant prostate cancer, the recommended initial dose of Octreotide-Long FS is 20 mg every 4 weeks for 3 months. In the future, the dose of the drug is corrected taking into account the dynamics of the concentration of prostate-specific antigen (PSA) in the serum, as well as clinical symptoms. If after 3 months of treatment failed to achieve an adequate clinical and biochemical effect (PSA reduction), the dose can be increased to 30 mg, administered every 4 weeks. Treatment with Octreotide-long FS is combined with the use of dexamethasone, which is prescribed by mouth as follows: 4 mg / day - for 1 month, then 2 mg / day for 2 weeks, then 1 mg / day (maintenance dose). Treatment of patients who had previously undergone drug-induced antiandrogen therapy are combined with the use of the GnRH analogue. In this case, an injection of the GnRH analogue (prolonged form) is carried out once every 4 weeks. Patients receiving Octreotide-Long FS, the determination of PSA concentrations should be carried out every month.

In patients with impaired renal function, liver and elderly patients, there is no need to correct the dosage regimen of Octreotide-long FS.

Rules for the preparation of suspension

1. The drug is administered only in / m.

2. The drug should be prepared and administered only by specially trained medical personnel.

3. The Octreotide-Long FS suspension is prepared immediately prior to administration with the aid of the supplied solvent.

4. Before injecting the ampoule with the solvent and the vial with the drug must be removed from the refrigerator and brought to room temperature (30-50 minutes is required).

5. The bottle with Octreotide-long FS must be kept strictly vertically! Tapping lightly on a vial, it is necessary to achieve, that all preparation was on the bottom of a vial

6. Open the package with the syringe, attach the supplied 0.8 × 40 mm needle to the solvent intake (use only the solvent included in the kit).

7. Open the ampoule with the solvent and draw into the syringe all the contents of the ampoule with the solvent, install the syringe to a dose of 2 ml

8. Remove the plastic cover from the vial with the active substance. Disinfect the rubber stopper with an alcohol swab (supplied in the package)

Insert the needle into the vial through the center of the rubber stopper. Do not touch the needle with the contents of the vial, carefully insert the solvent into the inner wall of the vial. Remove the syringe from the vial

9. Do not touch the bottle until the solvent has completely moistened the entire contents of the vial. After the contents of the vial are completely soaked with a solvent (this takes approximately 2-5 minutes), carefully, without turning the vial, check for a dry residue in the vial. If it is found, leave the vial until it is completely soaked

For 30-60 seconds, gently rotate the vial slowly until a uniform suspension forms. Do not overturn or shake the vial

10. Prepare the patient for injection.

11. Replace the needle on the syringe with a 1.2 × 50 mm needle (for slurry kit). Insert the needle through the rubber stopper into the vial. Then cut the needle cut down and, tilting the bottle at an angle of 45 °, slowly fill the syringe completely. Do not flip the bottle when typing. A small amount of the drug can remain on the walls and bottom of the vial. The consumption of the residue on the walls and the bottom of the vial is taken into account

12. Remove the needle immediately after dialing the suspension. Replace with a needle for the introduction of a drug measuring 1.1 × 40 mm, gently turn the syringe and remove air from the syringe.

13. Suspension of Octreotide-Long FS should be administered immediately after preparation.

14. Octreotide-Long FS suspension should not be mixed with any other medicinal substance in one syringe.

15. Disinfect the injection site. Insert the needle deep into the gluteus muscle, pull the plunger of the syringe towards you to make sure that the blood vessel is not damaged.

16. Introduce a slow suspension.

17. If you get into a blood vessel, you need to change the injection site and the needle.

18. If the needle is blocked, replace it with another one.

19. With repeated injections, the left and right sides should alternate.

Overdose

According to the known data, when octreotide was administered at a dose of 90 mg every 2 weeks in patients with malignant neoplasms, no undesirable phenomena were noted.

With a single intravenous bolus administration of octreotide at a dose of 1 mg, an adult patient described symptoms such as short-term bradycardia, flushing to the face, abdominal cramps, diarrhea, a feeling of emptiness in the stomach and nausea. All described symptoms resolved within 24 hours after drug administration.

Treatment: symptomatic.

special instructions

With pituitary tumors secreting GH, careful monitoring of patients is necessary, since it is possible to increase the size of the tumor 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. In 15-30% of patients receiving octreotide s / c for a long time, there may be the appearance of stones in the gallbladder. The prevalence in the general population (age 40-60 years) is 5-20%. The experience of long-term treatment with octreotide prolonged action of patients with acromegaly, with neuroendocrine tumors of the gastrointestinal tract and pancreas indicates that octreotide prolonged action in comparison with short-acting octreotide does not lead to an increased incidence of gallbladder stones. Nevertheless, it is recommended to have an ultrasound of the gallbladder before starting treatment with Octreotide-long FS and approximately every 6 months during treatment. Stones in the gallbladder, if nevertheless they are found, as a rule, are asymptomatic.

In patients with type 1 diabetes, Octreotide-long FS may affect glucose metabolism and, consequently, reduce the need for injected insulin. For patients with type 2 diabetes mellitus and patients without concomitant disturbance of carbohydrate metabolism, octreotide injections may result in postprandial glycemia. In this regard, it is recommended to regularly monitor the concentration of blood glucose and, if necessary, correct hypoglycemic therapy.

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 effect on the secretion of GH and glucagon than on insulin secretion, as well as a shorter duration of inhibitory effect on insulin secretion). A systematic observation of these patients is shown.

In some patients, octreotide can alter the absorption of fats in the intestine. Against the background of the use of octreotide, a decrease in the content of cyanocobalamin (vitamin B12) and a deviation from the norm of the indices of the cyanocobalamin absorption test (Shilling test).

In some patients, octreotide can alter the absorption of fats in the intestine. Against the background of the use of octreotide, a decrease in the content of cyanocobalamin (vitamin B12) and a deviation from the norm of the indices of the cyanocobalamin absorption test (Shilling test).

In patients with a vitamin B12 deficiency in the history of octreotide, it is recommended to monitor the content of cyanocobalamin.

Before the appointment of octreotide, patients should undergo ultrasound of the gallbladder. During treatment with Octreotide-long FS, 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 therapy with Octreotide-long FS compared to the possible risk associated with the presence of gallstones. At present, there is no evidence that octreotide prolonged action adversely affects the course or prognosis of an already existing cholelithiasis.

Management of patients whose gallstones are formed during treatment with Octreotide-long FS

1. Asymptomatic stones of the gallbladder. The use of Octreotide-long FS may be discontinued or continued in accordance with the benefit / risk ratio estimate. In any case, no other measures are required, except to continue inspections, making them, if necessary, more frequent.

2. Stones of the gallbladder with clinical symptoms. The use of Octreotide-long FS can be discontinued or continued - in accordance with 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.

Impact on the ability to drive and other vehicles, to work with moving mechanisms. To date, there is no evidence of the effect of octreotide on the ability to drive a car and work with mechanisms.

Form of issue

Microspheres for the preparation of suspension for intramuscular administration of prolonged action, 10 mg, 20 mg and 30 mg. In bottles of dark glass with a capacity of 10 ml.

2 ml of solvent (mannitol, 0.8% solution) in neutral glass ampoules. In the contour mesh package are placed: 1 fl. With the drug; 1 amp. With a solvent; 1 disposable syringe with a capacity of 5 ml; 1 sterile solvent needle, 0.8 mm × 40 mm in size; 1 sterile needle for suspension, size 1.2 mm × 50 mm; 1 sterile injection needle, 1.1 mm × 40 mm in size; 1 knife for opening ampoules or 1 scarifier; 2 alcohol wipes.

When you pack the solvent into imported ampoules that have an opening ring or a break point, the ampoule scapegrator or the opener for opening the ampoule do not.

1 circuit pack of the kit is placed in a cardboard pack.

Terms of leave from pharmacies

On prescription.

Storage conditions

In a dry, the dark place at a temperature of 2-8 ° C.

Keep out of the reach of children.

Shelf life

2 years. 6 months - lyophilizate, 6 h - finished product.

Do not use after the expiry date printed on the package.