Sandostatin LAR microspheres for sus. for the introduction of 20mg 2.5 ml №1

pharmachologic effect

Sandostatin^® LAR is a synthetic octapeptide that is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a much longer duration of action. Octreotide depot form inhibits pathologically increased secretion of growth hormone (GH), as well as the release of GH, caused by arginine, exercise and insulin hypoglycemia. The drug also inhibits the secretion of the peptides of the gastro-entero-pancreatic system (for example, the secretion of insulin, glucagon, gastrin) and serotonin caused by the ingestion of food. Also, octreotide depot form inhibits the secretion of insulin and glucagon, stimulated by arginine; thyrotropin secretion caused by thyroliberin.

Unlike somatostatin, octreotide inhibits GH secretion to a greater extent than insulin secretion, and its administration is not accompanied by a rebound effect in the form of hypersecretion of hormones (for example, GH in patients with acromegaly).

In patientsacromegaly the use of octreotide depot form ensures the maintenance of stable therapeutic concentrations of octreotide in serum with the introduction of the drug 1 time in 4 weeks.The introduction of octreotide depot form in most cases provides a persistent decrease in serum GH levels and normalization of serum insulin-like growth factor-1 (IGF-1).

In most patients with acromegaly, octreotide depot form significantly reduces the severity of symptoms such as headache, sweating, paresthesias, fatigue, pain in bones and joints, carpal tunnel syndrome. In some clinical cases, treatment with octreotide in a depot form of patients with pituitary adenomas secreting GH resulted in a reduction in the size of the tumor.

Atsecreting endocrine tumors of the digestive tract and pancreasthe use of octreotide depot form provides continuous monitoring of the main symptoms of these diseases.

Octreotide depot form at a dose of 30 mg every 4 weeks slows tumor growth in patients with secreting and non-secreting common (metastatic) neuroendocrine tumors of the skinny, iliac, blind,
ascending colon, transverse colon and the appendix, or metastases of neuroendocrine tumors without a primary lesion. The drug significantly increased the time to progression in this category of patients: the median time to progression was 14.3 months compared with 6 months in the placebo group. After 6 months of treatment, stabilization was observed in 66% of patients in the octreotide depot form and in 37% of patients in the placebo group.The drug was effective in increasing the time to progression, both for secreting and non-secreting neuroendocrine tumors.

Atcarcinoid tumors the use of octreotide can lead to a decrease in the severity of 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 urinary excretion of 5-hydroxyindole acetic acid.

AtTumors characterized by hyperproduction of vasoactive intestinal peptide (VIPomas), the use of octreotide leads in most patients to a reduction in severe secretory diarrhea, which 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 concomitant electrolyte imbalances, for example, hypokalemia, which allows you to cancel enteral and parenteral administration of fluid and electrolytes. According to computed tomography, in some patients, the progression of the tumor slows down or stops and even decreases in size, especially the metastatic foci in the liver. Clinical improvement is usually accompanied by a decrease (up to normal values) in the concentration of vasoactive intestinal peptide (VIP) in plasma.

Atglucagonomas the use of octreotide in most cases leads to a significant reduction in necrolytic migrating erythema, which is characteristic of this state.Octreotide does not have any significant effect on the severity of diabetes mellitus, often observed with glucagonomas, and its use usually does not reduce the need for insulin or oral hypoglycemic drugs. In patients with diarrhea, octreotide causes its decrease, which is accompanied by an increase in body weight. When using octreotide, there is often a rapid decrease in plasma glucagon concentration, but with long-term treatment this effect does not persist. At the same time, improvement of clinical symptoms persists for a long time.

Atgastrinomas / zollinger-ellison syndrome when using octreotide as monotherapy or in combination with histamine H blockers₂-receptors and proton pump inhibitors may reduce the formation of hydrochloric acid in the stomach and the development of clinical improvement, including the reduction of diarrhea. It is also possible to reduce the severity of other symptoms, probably associated with the synthesis of peptides by a tumor, incl. tides In some patients, there is a decrease in plasma gastrin concentration.

In patients with insulinomas Octreotide reduces the level of immunoreactive insulin in the blood.

In patients with operable tumors, octreotide can ensure the restoration and maintenance of normoglycemia in the preoperative period. In patients with inoperable benign and malignant tumors, glycemic control can be improved even without a simultaneous steady decrease in the level of insulin in the blood.

In patients with rare tumors that hyperproduce the releasing factor of growth hormone (somatoliberinomas), octreotide reduces the severity of the symptoms of acromegaly. This is apparently due to the suppression of secretion of the releasing factor of growth hormone and the growth hormone itself. In the future, it is possible to reduce the size of the pituitary gland, which was increased before the start of treatment.

Pharmacokinetics

After i / m administration of octreotide depot form, the concentration of octreotide in serum reaches a short-term initial peak within 1 hour and then progressively decreases within 24 hours until it reaches undetectable values. After the initial peak, marked on day 1, the concentration of octreotide in the next 7 days in most patients remains within the sub-therapeutic values. After that, the concentrations of octreotide increase again, reach a "plateau" by about the 14th day and remain relatively constant over the next 3-4 weeks. The value of the peak concentration on the first day is lower than the levels marked in the "plateau" phase. On the 1st day, no more than 0.5% of the total amount of the active substance is released. After about 42 days, octreotide concentrations slowly decrease, which occurs simultaneously with the final stage of degradation of the polymer matrix of the dosage form.

After administration of octreotide depo-form to patients with acromegaly in single doses of 10 mg, 20 mg and 30 mg, the concentration of octreotide in the plateau phase was 358 ng / l, 926 ng / l and 1710 ng / l, respectively. C_ssSerum octreotide, achieved after performing 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals, was approximately 1.6-1.8 times higher and amounted to 1557 ng / l and 2384 ng / l, respectively.

In patients with carcinoid tumors who underwent multiple injections of octreotide depo-form in doses of 10 mg, 20 mg and 30 mg at 4-week intervals, mean values ​​of C_ss Serum octreotide increased linearly with increasing dose and amounted to 1231 (894) ng / l, 2620 (2270) ng / l and 3928 (3010) ng / l, respectively.

When using octreotide depot form for 28 months (1 injection / month), no octreotide accumulation over the one that could be expected due to partial overlapping of the pharmacokinetic curves.

The pharmacokinetic profile of octreotide after injection of octreotide depot form reflects the profile of its release from the polymer matrix and its biodegradation. After entering the systemic circulation, the distribution of octreotide occurs in accordance with its pharmacokinetic properties, which are described for the dosage form for s / c administration. V_d octreotide in the equilibrium state is 0.27 l / kg. Total plasma clearance is 160 ml / min. Plasma protein binding is 65%. Octreotide does not bind to the blood cells.

Indications

Acromegaly treatment in the following cases:

- when adequate control of the manifestations of the disease is carried out due to sc injection of Sandostatin;

- in the absence of sufficient effect or with the complete ineffectiveness of surgical treatment or radiation therapy, as well as after radiation therapy as a short-term treatment until its effect fully develops.

Treatment of patients with symptoms of endocrine tumors of the gastrointestinal tract and pancreas, when s / c the introduction of Sandostatin provides adequate control of the manifestations of the disease:

- carcinoid tumors with manifestations of carcinoid syndrome;

- VIPomas;

- glucagonomas;

- gastrinomas / Zollinger-Ellison syndrome;

- insulinomas - to control hypoglycemia in the preoperative period, as well as for maintenance therapy;

- somatoliberinomas (tumors characterized by overproduction of growth hormone releasing factor).

Treatment of patients with secreting and non-secreting common (metastatic) neuroendocrine tumors of the jejunum, ileum, blind, ascending colon, transverse colon, vermiform process or
metastases of neuroendocrine tumors without initially identified lesion.

Dosing regimen

Sandostatin^® LAR should be injected only deeply in / m, in the gluteus maximus. With repeated injections, the left and right sides should be alternated.

Acromegaly

Forpatients in whom s / c administration of the drug Sandostatin^® provides adequate control of the manifestations of the disease,recommended starting dose of Sandostatin^® LAR is 20 mg every 4 weeks for 3 months. Start treatment with Sandostatin^® LAR can be the day after the last p / to the introduction of Sandostatin. In the future, the dose is corrected taking into account the concentration in serum GH and IGF 1, as well as clinical symptoms. If after 3 months of treatment it was not possible 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.

If after 3 months of treatment it was not possible to achieve an adequate clinical and biochemical effect (elevated levels of GH and IGF-1), the dose can be increased to 40 mg every 4 weeks.

In cases where, after 3 months of treatment with Sandostatin^® LAR at a dose of 20 mg shows a persistent decrease in the serum concentration of GH below 1 µg / l, normalization of the concentration of IGF 1 and the disappearance of the reversible symptoms of acromegaly, can reduce the dose of the drug Sandostatin^® LAR up to 10 mg every 4 weeks. However, in these patients receiving a relatively small dose of Sandostatin^® LAR, should continue to closely monitor serum concentrations of GH and IGF 1, as well as disease symptoms.

Patients receiving a stable dose of Sandostatin^® LAR, determination of concentrations of GH and IGF 1 should be carried out every 6 months.

For patients in whom surgical treatment and radiation therapy are not effective enough or are not effective at all, as well as for patients who need short-term treatment after a course of radiation therapy until its full effect develops,It is recommended to conduct a short trial course of treatment with Sandostatin injections to evaluate its efficacy and general tolerability, and only after that switch to the use of Sandostatin^® LAR according to the above scheme.

Endocrine tumors of the gastrointestinal tract and pancreas

For patients in whom s / c administration of the drug Sandostatin^® provides adequate control of disease manifestationsrecommended starting dose of Sandostatin^® LAR is 20 mg every 4 weeks. P / to the introduction of the drug Sandostatin^® should be continued for another 2 weeks after the first injection of the drug Sandostatin^® LAR.

Forpatients not previously treated with SandostatinIt is recommended to start treatment with the administration of Sandostatin at a dose of 0.1 mg 3 times / day for a short period (approximately 2 weeks) in order to assess its effectiveness and overall tolerance. Only after this is prescribed Sandostatin^® LAR according to the above scheme.

In case when therapy with Sandostatin^® LAR for 3 months provides adequate control of clinical manifestations and biological markers of the disease, you can reduce the dose of the drug Sandostatin^® LAR up to 10 mg every 4 weeks.

In cases where, after 3 months of treatment with Sandostatin LAR, only partial control of symptoms was achieved, the dose of the drug can be increased to 30 mg every 4 weeks.

Against the background of treatment with Sandostatin^® LAR on some days may increase the clinical manifestations characteristic of endocrine tumors of the gastrointestinal tract and pancreas.This can occur mainly in the first 2 months of treatment, until therapeutic plasma concentrations of octreotide are reached. In these cases, an additional subcutaneous injection of Sandostatin is recommended at the dose used before starting treatment with Sandostatin.^® LAR.

Secreting and non-secreting common (metastatic) neuroendocrine tumors of the jejunum, ileum, blind, ascending colon, transverse colon and the appendix, or metastasis of neuroendocrine tumors without initially identified outbreak

The recommended dose of Sandostatin^® LAR is 30 mg every 4 weeks. Therapy with Sandostatin^® LAR should be continued until signs of tumor progression.

Renal dysfunction do not affect octreotide AUC. When using the drug Sandostatin^® LAR in patients with impaired renal function, correction of its dose is not required.

Liver dysfunction. The results of the study, in which s / c and intravenous injection of Sandostatin were used, showed that a slowdown in the elimination of the drug may occur in patients with cirrhosis of the liver, but this is not observed in patients with fatty hepatosis. Due to the wide therapeutic range of octreotide, there is no need to correct the dosage regimen of the drug Sandostatin^® LAR in patients with cirrhosis of the liver.

The results of a study in which Sandostatin was injected s / c to patients aged 65 years and older showed that there is no need to change the dosage regimen of the drug inelderly patients. Similarly, in this category of patients is not required to adjust the dose of the drug Sandostatin^® LAR.

Terms of preparation of suspension for injection and drug administration

The following recommendations should be strictly followed. To enter only homogeneous suspension. Suspension Sandostatin^® LAR is preparingimmediately before the introduction. Sandostatin^® LAR should only prepare and administer specially trained medical personnel.

Withstand a bottle of Sandostatin LAR powder and a syringe with a solvent at room temperature. Remove cap from vial containing sandostatin^®LAR. Lightly tapping the bottle should ensure that the powder is evenly distributed across the bottom of the bottle. The bottle should be kept strictly vertically.

Remove the syringe tip with the solvent. Put the attached needle on the syringe.

Disinfect the rubber stopper of the bottle with an alcohol swab. Insert the needle into the vial of Sandostatin LAR, piercing through the center of the rubber stopper. Without touching the contents of the vial with the needle, carefully introduce the solvent along the inner wall of the vial. Do not inject solvent directly into the powder. Remove the syringe from the vial.

It is necessary that the vial remains stationary until complete impregnation of the powder contained in the vial with the solvent occurs to form a suspension. After the solvent has completely soaked the powder (in about 2-5 minutes), without turning the bottle, you should check the presence of a dry powder at the walls and bottom of the bottle. If dry powder remains, leave the vial left until it is completely soaked.At this time, the patient should be prepared for the injection.

After ensuring that there is no residue of dry powder, the vial should be gently rotated for 30-60 seconds until a homogeneous suspension is formed. The bottle can not be shaken, it can lead to precipitation of flakes and unsuitability of the suspension.

Quickly insert the needle through the rubber stopper into the vial. Then, having lowered a cut of a needle down and having inclined a bottle at an angle 45 °, slowly to collect in suspension the syringe completely. It is impossible to turn over a bottle when filling the syringe - it can affect the selected quantity. Some small amount of suspension may remain on the walls and bottom of the bottle. This is a normal phenomenon, the flow rate on the residue on the walls and bottom of the bottle is taken into account.

Immediately change the needle on the syringe (the second needle from the package).

Suspension should be administered immediately after preparation. Gently invert the syringe to achieve a uniform suspension. Remove air from a syringe. Alcohol swab disinfect injection site. Insert the needle deep into the gluteus muscle, then slightly pull the plunger of the syringe back to make sure that there is no damage to the vessel. Inject the suspension in / m slowly with constant pressure on the syringe plunger. When blocking the needle, replace it with another needle of the same diameter.

Sandostatin^® LAR should be injected deep into the gluteus maximus muscle. You can not enter in / in. If it enters the blood vessel, the needle and the injection site should be changed.