Oktreotid-long FS

General characteristics. Structure:

Active ingredient: 10 mg, 20 mg or 30 mg of an okreatid in the form of microspheres.

Excipients: DL milk and glycolic acids copolymer, D-Mannitolum, karmelloza of sodium, polysorbate 80.

Solvent: transparent colourless liquid.

The recovered suspension: at addition of solvent and agitation homogeneous suspension of color, white or white with a weak yellowish shade, has to be formed; when standing suspension is besieged, but easily resuspended when stirring; suspension has to pass freely in the syringe through a needle No. 0840.

Pharmacological properties:

Pharmacodynamics. Oktreotid — synthetic octapeptide, derivative natural hormone of somatostatin, having pharmacological effects, similar to it, but with considerably bigger duration of action. Oktreotid suppresses patholologically hypersecretion of the growth hormone (GH), and also the peptides and serotonin produced in gastroenteropankreatichesky endocrine system.

At healthy faces октреотид, like somatostatin, suppresses the secretion of GR caused by arginine, an exercise stress and an insulin hypoglycemia; the secretion of insulin, a glucagon, gastrin and other peptides of gastroenteropankreatichesky endocrine system caused meal and also the secretion of insulin and a glucagon stimulated by arginine; the thyrotropin secretion caused tireoliberiny. Overwhelming action on secretion of GR at an oktreotid, unlike somatostatin, is expressed in much bigger degree, than on insulin secretion. Introduction of an oktreotid is not followed by a phenomenon of hypersecretion of hormones on a negative feedback mechanism.

At patients with an acromegalia introduction of an oktreotid provides in most cases permanent decrease in the GR level and normalization of concentration of an insulinopodobny growth factor 1 (IFR-1). At patients with an acromegalia октреотид significantly reduces expressiveness of such symptoms as a headache, the increased sweating, paresthesias, fatigue, an ostealgia and joints, peripheral neuropathy. At patients with the adenoma of a hypophysis cosecreting GR leads to reduction of the sizes of a tumor.

At carcinoid tumors use of drug leads to reduction of expressiveness of symptoms of a disease, first of all such as rushes of blood to a face and diarrhea. In many cases clinical improvement is followed by decrease in concentration of serotonin in plasma and excretion of 5-hydroxyindolacetic acid with urine.

At the tumors which are characterized by hyperproduction of the vasoactive intestinal peptide (VIP), use of an oktreotid leads to reduction of the heavy secretory diarrhea characteristic of this state that, in turn, improves quality of life of the patient. At the same time there is a reduction of the accompanying disturbances of electrolytic balance, for example hypopotassemias that allows to cancel enteral and parenteral administration of liquid and electrolytes. According to a computer tomography patients have a delay or a stop of progressing of growth of a tumor, and even reduction of its sizes, especially metastasises in a liver. Clinical improvement usually is followed by reduction (up to normal values) concentration the VIP in plasma.

At glucagonomas use of an oktreotid leads to noticeable reduction of the necrotizing migrating rash which is characteristic of this state. Oktreotid has no a little significant effect on expressiveness of the diabetes mellitus which is often observed at glucagonomas and usually does not lead to decrease in need for insulin or peroral hypoglycemic drugs. At the patients having diarrhea, drug causes its reduction that is followed by increase in body weight. At use of an oktreotid there is a bystry decrease in concentration of a glucagon in plasma, however at prolonged treatment this effect does not remain. Symptomatic improvement remains stable a long time.

At gastrinoma (Zollingera-Ellison's syndrome) the drug used as monotherapy or in a combination with H2 blockers - histamine receptors and inhibitors of the proton pump, reduces formation of hydrochloric acid in a stomach and leads to clinical improvement, including and concerning diarrhea. At introduction of an oktreotid there is a reduction of expressiveness of the symptoms connected with synthesis of peptides a tumor including rushes of blood to the person. Decrease in concentration of gastrin in plasma is in certain cases noted.

At patients from insulinoma октреотид reduces the content of immunoreactive insulin in blood.

At patients with resectable tumors октреотид can provide recovery and maintenance of a normoglikemiya in the preoperative period. At patients with nonresectable benign and malignant tumors control of a glycemia can improve also without simultaneous long decrease in concentration of insulin in blood.

At patients with seldom found tumors which are hyper producing a rileasing-factor of a growth hormone (somatoliberinomama) октреотид reduces acromegalia symptoms that is connected with suppression of secretion of a rileasing-factor of a growth hormone and GR. Thus, in the subsequent there is a reduction of the sizes of a hypophysis which prior to treatment were increased.

At patients with a gormonorezistentny prostate cancer (GRRPZh) the pool of the neuroendocrinal cells expressing somatostatinovy receptors, affine to an oktreotid (SS2-and SS5 types) that defines sensitivity of a tumor to an oktreotid increases. Use of an oktreotid in a complex with dexamethasone against the background of androgenic blockade (medicamentous or surgical castration) at patients of GRRPZh recovers sensitivity to hormonal therapy and leads to decrease in the prostatic specific antigen (PSA) more than at 50% of patients. At patients of GRRPZh with metastasises in a bone this therapy is followed by the expressed and long-term analgesic effect, quality of life improves.

Pharmacokinetics. After п / to introduction absorption - bystry and full. TCmax (5.2 mg/ml at a dose of 0.1 mg) - 30 min. Communication with proteins of plasma - 65%, with uniform elements of blood - extremely insignificant. The volume of distribution makes 0.27 l/kg. The general clearance - 160 ml/min.

T1/2 - 100 min. About 32% are removed in not changed look by kidneys. Later in/in introductions removal is carried out in 2 phases, with T1/2 - 10 and 90 min. according to. At elderly patients the clearance of an oktreotid decreases, and T1/2 increases. At heavy HPN the clearance decreases twice.

Indications to use:

Oktreotid is cure of pathogenetic therapy for the tumors which are actively expressing receptors to somatostatin.

In therapy of an acromegalia:

- when adequate control of displays of a disease is exercised due to hypodermic introduction of an oktreotid;
- in the absence of sufficient effect of surgical treatment and radiation therapy;
- for preparation for surgical treatment;
- for treatment between courses of radiation therapy before development of lasting effect;
- at inoperable patients.

In therapy of endocrine tumors of the digestive tract (DT) and pancreas:

- carcinoid tumors with the phenomena of a carcinoid syndrome;
- insulinoma;
- Vipoma;
- gastrinoma (Zollingera-Ellison's syndrome);
- glucagonomas (for control of a hypoglycemia in the preoperative period, and also for a maintenance therapy);
- somatoliberinoma (the tumor which are characterized by hyperproduction rileasing-a growth hormone factor).

In therapy of a gormonorezistentny prostate cancer:

- as a part of a combination therapy against the background of surgical or medicamentous castration.

Route of administration and doses:

The drug "Oktreotid-long FS" should be administered only deeply intramusculary, in a gluteus. At repeated injections the left and right parties should be alternated. Suspension should be prepared just before an injection. In day of an injection the bottle with drug and an ampoule with solvent can be held at the room temperature.

At an acromegalia for the solution of a question concerning portability and efficiency of prolonged treatment of Oktreotidom-long of FS it is recommended to prepost 3-day test with hypodermic introduction of an oktreotid (300 mkg/days). Decrease in the IFR-1 level in blood from initial (in the absence of intolerance signs) will indicate more than 60% the good forecast of use of drug as long primary or secondary pharmacotherapy. For the patients less sensitive to drug, the starting dose has to be higher. For resistant group of patients surgical intervention is recommended. In case of not radical adenomectomy 3-day test with hypodermic introduction increases sensitivity to the subsequent medicinal therapy.

For patients at whom п / to introduction of an oktreotid provides adequate control of displays of a disease the recommended initial dose of the drug "Oktreotid-long FS" makes 20 mg each 4 weeks within 3 months.

It is possible to begin treatment of Oktreotidom-long of FS next day after the last p / to administration of solution of an oktreotid. Further the dose of drug is korrigirut taking into account concentration in GR and IFR-1 serum, and also clinical symptoms.

If after 3 months of treatment it was not succeeded to reach adequate clinical and biochemical effect (in particular if concentration of GR remains higher than 2,5 mkg/l), it is possible to increase a dose to 30 mg entered each 4 weeks.

When after 3 months of treatment the drug "Oktreotid-long FS" in a dose of 20 mg notes permanent reduction of serumal concentration of GR lower than 1 mkg/l, normalization of concentration of IFR-1 and disappearance of reversible symptoms of an acromegalia, it is possible to reduce a dose of Oktreotida-long of FS to 10 mg. However at these patients receiving rather small dose of Oktreotida-long of FS it is necessary to continue to control carefully serumal concentration of GR and IFR-1, and also disease symptoms. To the patients receiving a stable dose of drug, definition of concentration of GR and IFR-1 it is necessary to spend each 6 months.

At endocrine tumors of a GIT and pancreas for patients at whom п / to introduction of an oktreotid provides adequate control of displays of a disease the recommended initial dose of Oktreotida-long of FS makes 20 mg each 4 weeks. Hypodermic introduction of an oktreotid should be continued within 2 weeks after the first introduction of Oktreotida-long of FS. For the patients who were not receiving earlier октреотид п / to it is recommended to begin treatment with п / to introduction of an oktreotid in a dose of 100 mkg of 3 times/days during rather short span (about 2 weeks) for the purpose of assessment of its efficiency and the general portability. Only after that appoint Oktreotid-long of FS according to the above-stated scheme. In case therapy of Oktreotidom-long of FS within 3 months provides adequate control of clinical manifestations and biological markers of a disease, it is possible to lower a dose of Oktreotida-long of FS to 10 mg appointed each 4 weeks. When after 3 months of treatment of Oktreotidom-long of FS it was succeeded to reach only partial improvement, it is possible to increase a dose of drug to 30 mg each 4 weeks. Against the background of treatment of Oktreotidom-long of FS in separate days strengthening of the clinical manifestations characteristic of endocrine tumors of a GIT and pancreas is possible.

In these cases it is recommended additional п / to administration of solution of an oktreotid in the dose applied prior to treatment of Oktreotidom-long of FS. It can occur, mainly, in the first 2 months of treatment, therapeutic concentration of an oktreotid in plasma are not reached yet.

At a gormonorezistentny prostate cancer the recommended initial dose of the drug "Oktreotid-long FS" makes 20 mg each 4 weeks within 3 months. Further the dose of drug is korrigirut taking into account dynamics of concentration of prostatospetsifichesky antigen (DOG) in serum, and also clinical symptoms. If after 3 months of treatment it was not succeeded to reach adequate clinical and biochemical effect (decrease in the DOG), it is possible to increase a dose to 30 mg entered each 4 weeks. Treatment of Oktreotidom-long of FS is combined using dexamethasone which is appointed inside according to the following scheme: 4 mg a day within 1 month, then 2 mg a day within 2 weeks, then 1 mg a day (maintenance dose). Treatment of patients by which carried out medicamentous anti-androgenic therapy earlier combine a gonadotrophin-rileasing of hormone (GNRG) using an analog. At the same time GNRG analog injection (the prolonged form) carry out 1 time in 4 weeks. To the patients receiving Oktreotid-long of FS, it is necessary to carry out definition of concentration of the DOG every month.

Patients with a renal failure, and at patients of advanced age have a liver no need to korrigirovat the mode of dosing Oktreotida-long of FS.

Rules of preparation of suspension:

• The drug is administered only intramusculary.
• Drug has to prepare and be entered by only specially trained medical personnel.
• FS Oktreotida-long suspension is prepared just before introduction by means of the enclosed solvent.
• Before an injection the ampoule with solvent and a bottle with drug needs to be got from the refrigerator and to bring to room temperature (30-50 min. are required).
• FS discipline a bottle with Oktreotidom-long vertically! Easily tapping on a bottle, achieve that all drug was at the bottom of a bottle.
• Open packaging with the syringe, attach to it the enclosed needle of 0,8 mm x 40 mm in size for a solvent intake (to use only the solvent which is included in the package).
• Open an ampoule with solvent and gather in the syringe all contents of an ampoule with solvent, install the syringe on a dose of 2 ml.
• Remove a plastic cover from a bottle with microspheres. Disinfect a rubber bung a spirit tampon (it is applied in packaging). Insert a needle into a bottle through the center of a rubber bung. Without concerning a bottle contents needle, carefully enter solvent on an internal wall of a bottle. Take out the syringe from a bottle.
• Do not touch a bottle until solvent does not moisten completely all contents of a bottle. After bottle contents completely became impregnated with solvent (it approximately takes 2-5 minutes), it is necessary carefully, without overturning a bottle, to check existence of the dry rest in a bottle. At detection, leave a bottle before full treatment. Within 30-60 seconds carefully slowly rotate a bottle before formation of homogeneous suspension. Do not overturn and do not stir up a bottle!
• Prepare the patient for an injection.
• Replace a needle on the syringe with a needle of 1,2 mm x 50 mm in size (for a set of suspension). Insert a needle through a rubber bung into a bottle. Then lower a cut of a needle down and, having inclined a bottle at an angle of 45 degrees, slowly gather in the syringe suspension completely. Do not overturn a bottle at set. A small amount of drug can remain on walls and day of a bottle. The expense on the rest on walls and day of a bottle is considered. Right after a set of suspension remove a needle. Replace with a needle for administration  of drug of 1,1 mm x 40 mm in size, accurately turn the syringe and remove air from the syringe.
• You enter FS Oktreotida-long suspension immediately after preparation.
• FS Oktreotida-long suspension should not mix up with any other medicinal substance in one syringe.
• Disinfect the place of an injection. Enter a needle deeply into a gluteus, pull the syringe piston on yourself to be convinced that the blood vessel is not damaged.
• Enter slowly suspension.
• At hit in a blood vessel it is necessary to change the place of an injection and a needle.
• At obstruction of a needle replace it another.
• At repeated injections the left and right parties should be alternated.

Features of use:

Use during pregnancy and breastfeeding. Experience of use of drug at pregnancy and during breastfeeding is absent therefore this category of patients drug is appointed only in urgent cases.

Use for children. There is a limited experience of use for children.

At the tumors of a hypophysis cosecreting GR careful observation of patients as increase in the sizes of a tumor with development of such serious complications as narrowing of fields of vision is possible is necessary. In these cases it is necessary to consider need of use of other methods of treatment. At 15 – 30% of the patients receiving октреотид п / to for a long time emergence of stones in a gall bladder is possible. Prevalence in the general population (age of 40-60 years) makes 5-20%. Experience of prolonged treatment oktreotidy the prolonged action of patients with an acromegalia, with neuroendocrinal tumors of a GIT and pancreas demonstrates to what октреотид the prolonged action in comparison with oktreotidy does not lead short action to increase in frequency of formation of stones of a gall bladder. Nevertheless, performing ultrasonography of a gall bladder before an initiation of treatment of Oktreotidom-long of FS and approximately in the course of treatment is recommended each 6 months. Stones in a gall bladder if after all they are found, as a rule, asymptomatic.

At patients with a diabetes mellitus of 1 FS Oktreotid-long type can influence exchange of glucose and, therefore, reduce the need for the entered insulin. For patients with a diabetes mellitus 2 types and patients without the accompanying disturbance of carbohydrate metabolism subcutaneous injections of an oktreotid can lead to a postprandialny glycemia. In this regard it is regularly recommended to control concentration of glucose of blood and in case of need to korrigirovat hypoglycemic therapy.

At patients from insulinoma against the background of treatment oktreotidy increase in expressiveness and duration of a hypoglycemia can be noted (it is connected with more expressed overwhelming influence on secretion of GR and a glucagon, than on insulin secretion, and also with the smaller duration of the inhibiting impact on insulin secretion). Systematic observation of these patients is shown.

At some patients октреотид can change absorption of fats in intestines.

Against the background of use of an oktreotid decrease in content of cyanocobalamine (B12 vitamin) and an aberration of indicators of the test of absorption of cyanocobalamine (the test of Shilling) is noted.

At patients with deficit of B12 vitamin in the anamnesis at use of an oktreotid it is recommended to control the content of cyanocobalamine.

Before purpose of an oktreotid patients have to undergo ultrasonography of a gall bladder. During treatment of Oktreotidom-long of FS it is necessary to carry out repeated ultrasonography of a gall bladder, preferably, bucketed 6 – 12 months. If stones of a gall bladder are found even prior to treatment, it is necessary to estimate potential advantages of therapy of Oktreotidom-long of FS in comparison with the possible risk connected with existence of gallstones. Now there are no certificates that октреотид the prolonged action adversely influences the current or the forecast of already available cholelithiasis.

Maintaining patients at whom stones of a gall bladder are formed in the course of treatment of Oktreotidom-long of FS.
a) Asymptomatic stones of a gall bladder. Use of Oktreotida-long of FS can be stopped or continued – according to ratio assessment advantage/risk. Anyway no other measures, except continuation of carrying out surveys are required, having made them, if necessary, more frequent.
b) Stones of a gall bladder with clinical symptomatology. Use of Oktreotida-long of FS can be stopped or continued – according to ratio assessment advantage/risk. Anyway the patient should be treated as well as in other cases of cholelithiasis with clinical manifestations.

Influence on ability to driving and other vehicles, for work with the moving mechanisms: today there are no data on influence of an oktreotid on ability to drive the car and to work with mechanisms.

Side effects:

Criteria for evaluation of frequency of development of undesirable reactions: very often (≥1/10); often (≥1/100, <1/10); sometimes (≥1/1000, <1/100); seldom (≥1/10000, <1/1000); very seldom (<1/10000), including separate messages.

Local reactions: often at introduction in oil are possible pain, the swelling and rashes in the place of an injection are more rare (as a rule, are poorly expressed, short).

From the alimentary system: often – spastic abdominal pains, abdominal distention, excess gas generation, a liquid chair, diarrhea; sometimes – cholecystitis; seldom – nausea, vomiting, formation of stones in a gall bladder, a steatorrhea. Though release of fat with a stake can increase, there are no instructions on the fact that prolonged treatment oktreotidy can lead to disturbance of absorption (malabsorption). In rare instances – the phenomena reminding acute intestinal impassability: the progressing abdominal distention, the expressed pain in epigastric area, tension of an abdominal wall. It was reported about exceptional cases of the acute pancreatitis which developed during the first hours or days п / to use of an oktreotid. At prolonged use cases of the pancreatitis connected with a cholelithiasis were noted.

There are separate messages on development of abnormal liver functions (an acute hepatitis without cholestasia with normalization of indicators of transaminases after cancellation of an oktreotid); the slow development of a hyperbilirubinemia which is followed by increase in indicators of an alkaline phosphatase gamma глутамилтрансферазы.

From endocrine system: in rare instances the resistant hyperglycemia, a hypoglycemia can develop.

From cardiovascular system: sometimes – bradycardia, tachycardia.

From respiratory system: very seldom – an asthma.

Allergic reactions: seldom - hypersensitivity, rash; very seldom – an anaphylaxis.

Others: it was in rare instances reported about a temporary hair loss after introduction of an oktreotid.

Interaction with other medicines:

Oktreotid reduces absorption from intestines of cyclosporine and slows down absorption of Cimetidinum. At simultaneous use of an oktreotid and Bromocriptinum bioavailability of the last increases.

There are literary data that analogs of somatostatin can reduce metabolic clearance of the substances which are metabolized P450 cytochrome enzymes that can be caused by GR suppression. As it is impossible to exclude the similar effects of an oktreotid, drugs which are metabolized enzymes of system of P450 cytochrome and having the narrow therapeutic range of doses (for example, quinidine and терфенадин) it is necessary to appoint with care.

Contraindications:

Hypersensitivity to an oktreotid or other components of drug.

With care:

- cholelithiasis,
- diabetes mellitus.

Overdose:

According to the known data, at use of an oktreotid in a dose of 90 mg each 2 weeks at patients with malignant new growths any undesirable phenomena were not noted. At single in bolyusny introduction of an oktreotid in a dose of 1 mg to the adult patient such symptoms as short-term bradycardia, "inflows" of blood to the person, spastic abdominal pains, diarrhea, feeling of emptiness in a stomach and nausea are described. All described symptoms were resolved within 24 hours after administration of drug.

Treatment: symptomatic.

Storage conditions:

In the dry, protected from light place at a temperature from 2 to 8 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

The microspheres for preparation of suspension for intramuscular introduction of the prolonged action containing 10 mg, 20 mg and 30 mg of an oktreotid in bottles from dark glass and in a cardboard pack.