Octreotide-long FS - instructions for use, dose, side effects, contraindications

Reduced suspension: when adding a solvent and stirring, a homogeneous suspension of white or white with a slight yellowish hue 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.

Pharmacotherapeutic group:Somatostatin analogue synthetic

ATX: & nbsp

H.01.C.B.02 Octreotide

Pharmacodynamics:Octreotide-long FS is a long-acting octreotide dosage form for intramuscular administration that maintains stable therapeutic octreotide concentrations in the blood for 4 weeks. Octreotide - synthetic octapeptide,a derivative of the natural hormone somatostatin, which has similar pharmacological effects, but a much longer duration of action. Octreotide Suppress 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 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.

With carcinoid tumors, the use of the drug leads 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 plasma serotonin concentration 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 the metastases in 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 in glucagonomes, and usually does not lead to a decrease in the need for insulin or oral hypoglycemic drugs. In patients with diarrhea, the drug causes a decrease in it, which is accompanied by an increase in body weight. When octreotide is used, the glucagon concentration in the plasma decreases rapidly, but with long-term 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 blockers H₂-gistaminovyh receptors and proton pump inhibitors, reduces the formation of hydrochloric acid in the stomach and leads to clinical improvement, including in relation to diarrhea.When octreotide is administered, the symptoms associated with the synthesis of peptides by the tumor, including "hot flashes", decrease. 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-producing growth hormone releasing factor (somatoliberinomas), octreotide reduces the symptoms of acromegaly, which is associated with the suppression of the secretion of the growth hormone releasing factor and the 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 (HRPC), 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.Use of the complex of octreotide with dexamethasone on androgen blockade (medical or surgical castration) in patients with PCa GR restores sensitivity to hormone therapy and leads to lower prostate specific antigen (PSA) for more than 50% of patients. Patients GR prostate cancer with bone metastases, this therapy is accompanied by a pronounced and long-lasting analgesic effect, improving the quality of life.

Indications:

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

In the therapy of acromegaly:

- when adequate control of 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 therapy of endocrine tumors of the gastrointestinal tract (GIT) 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.

Carefully:Chololithiasis, diabetes mellitus.

Pregnancy and lactation:

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

Dosing and Administration:

The drug "Octreotide-Long FS" should be administered only deep intramuscularly, in the gluteal 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.

With acromegaly to address the issue of the tolerability and effectiveness of long-term treatment with Octreotide-long FSit is recommended to carry out a 3-day trial with subcutaneous administration of octreotide (300 μg / day). The decrease in IGF-1 level in the blood of 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 subcutaneous injection 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 Octreotide-FS is 20 mg every 4 weeks for 3 months. You can start treatment with Octreotide-Long FS the day after the last o / w 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 an adequate clinical and biochemical effect could not be achieved (in particular, if the GH concentration 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 a 20 mg dose of Octreotide-Long FS, 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.

When 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. Subcutaneous 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 n / k, it is recommended to start treatment with the SC administration of octreotide at a dose of 100 μg 3 times / day for a relatively short period of time (approximately 2 weeks) in order to evaluate its effectiveness and overall tolerance.Only after this, Octreotide-long FS is prescribed 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, the clinical manifestations characteristic of endocrine tumors of the gastrointestinal tract and pancreas may increase. In these cases, an additional SC administration of an octreotide solution is recommended in the dose used before the start of treatment with Octreotide-long FS. This can occur mainly in the first 2 months of treatment, until the therapeutic concentrations of octreotide in plasma are reached.

When 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 per day for 1 month, then 2 mg per day for 2 weeks, then 1 mg per day (maintenance dose). Treatment of patients who had previously undergone drug-induced antiandrogen therapy is combined with the use of a gonadotropin-releasing hormone (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, hepatic and elderly patients, there is no need to correct the dosage regimen of Octreotide-long FS.

Rules for the preparation of suspension

- The drug is administered only intramuscularly.

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

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

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

- Keep the bottle with Octreotide-long FS strictly vertically! Tapping lightly on the vial, make sure that the entire preparation is on the bottom of the vial.

- Open the package with a syringe, attach the supplied 0.8 mm x 40 mm needle to the solvent intake (use only the solvent supplied).

- Open the ampoule with the solvent and put into the syringe all the contents of the ampoule with the solvent, install the syringe on a dose of 2 ml.

- Remove the plastic cover from the vial with microspheres. Disinfect the rubber stopper with an alcohol swab (supplied in the package). Insert the needle into the bottle through the center of the rubber stopper. Without touching 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.

- Do not touch the bottle until the solvent has completely moistened the entire contents of the vial. After the contents of the bottle 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 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 bottle!

- Prepare the patient for injection.

- Replace the needle on the syringe with a needle measuring 1.2 mm x 50 mm (for a set of slurry). Insert the needle through the rubber stopper into the vial. Then cut the needle cut down and, tilting the vial at an angle of 45 degrees, slowly put the suspension in 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.

Immediately after the suspension is removed, remove the needle. Replace on the needle for the introduction of the drug size of 1.1 mm x 40 mm, gently flip the syringe and remove the syringe air.

- Suspension of Octreotide-Long FS is given immediately after preparation.

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

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

- Enter the suspension slowly.

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

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

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

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 the / m introduction, pain is possible, less swelling and rashes at the injection site (usually mild, short).

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). In rare cases - phenomena that resemble acute intestinal obstruction: progressive bloating, severe pain in the epigastric region, stress of the abdominal wall. There have been reports of rare cases of acute pancreatitis that developed in 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); slow development of hyperbilirubinemia, accompanied by an increase in the parameters of alkaline phosphatase, gamma-glutamyltransferase.

From the endocrine system: in rare cases, persistent hyperglycemia, hypoglycemia may develop.

From the cardiovascular system: sometimes bradycardia, tachycardia.

From the respiratory system: very rarely - dyspnea.

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

Other: In rare cases, a temporary hair loss after octreotide administration was reported.

Overdose:

According to known data, no adverse events were observed with octreotide at a dose of 90 mg every 2 weeks in patients with malignant tumors.

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

Treatment: symptomatic.

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 range of doses (for example, quinidine and terfenadine) should be administered with caution.

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 the fields of vision.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, possibly the appearance of stones in the gallbladder. The prevalence in the general population (age 40-60 years) is 5-20%. Long-term treatment with octreotide prolonged action of patients with acromegaly, with neuroendocrine tumors and pancreas testifies that octreotide prolonged action in comparison with short-acting octreotide does not lead to an increase in the frequency of gallbladder stones formation. Nevertheless, it is recommended that ultrasound of the gallbladder be performed before the beginning of treatment with Octreotide-long FS and approximately every 6 months during the 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 influence 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, subcutaneous octreotide injections can lead to 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, an increase in the severity and duration of hypoglycemia may occur in patients with insulinomas (this is associated with a more pronounced suppressive effect on GH and glucagon secretion than on insulin secretion, and also with a shorter duration of inhibitory effect on insulin secretion). A systematic observation of these patients is shown.

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

In patients with vitamin B deficiency₁₂ in the history of the use of octreotide 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 6-12 months.If gallbladder stones are found even before the start of treatment, it is necessary to evaluate the potential benefits of Octreotide-long FS therapy compared to the possible risk associated with the presence of gallstones. At the present time, 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

a) Asymptomatic stones of the gallbladder.

The use of Octreotide-long FS can 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.

b) 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.

Use in children

There is limited experience in children

Effect on the ability to drive transp. cf. and fur:To date, there is no evidence of the effect of octreotide on the ability to drive a car and work with mechanisms.

Form release / dosage:

Microspheres for suspension preparation for intramuscular administration of prolonged actions containing 10 mg, 20 mg and 30 mg of octreotide.

Packaging:

ATo bottles of dark glass with a capacity of 10 ml. 2 ml of solvent (mannitol, 0.8% solution) into ampoules neutral glass.

In production at Ltd "Nativa", Russia indicate:

The following is placed in the contour cell package:

1 bottle with the drug;

1 ampoule with solvent;

1 disposable syringe with a capacity of 5 ml;

1 sterile solvent needle, 0.8 mm x 40 mm;

1 sterile needle for suspension, 1.2 mm x 50 mm;

1 sterile injection needle, measuring 1.1 mm x 40 mm;

1 knife for opening ampoules or 1 scarifier;

2 alcohol wipes.

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

1 circuit cell pack together with the instruction for use is placed in a cardboard pack.

Or, when manufacturing at OAO Pharmstandard-UfaVITA, Russia indicates: