Description
Latin name
SANDOSTATIN LAR
Release form
Microspheres for preparing a suspension for i / m administration.
Packaging
In a bottle of 5 ml. In a cardboard box 1 bottle complete with solvent and sterile needles.
Pharmacological action
Pharmacodynamics
Sandostatin ® LAR is a synthetic octapeptide that is a derivative of the natural hormone somatostatin and has similar pharmacological effects, but a significantly longer duration of action. Octreotide depot suppresses pathologically increased secretion of growth hormone (GH), as well as the release of GH caused by arginine, exercise, and insulin hypoglycemia. The drug also suppresses the secretion of peptides of the gastro-entero-pancreatic system (for example, the secretion of insulin, glucagon, gastrin caused by food intake) and serotonin. Octreotide depot also suppresses the secretion of insulin and glucagon, stimulated by arginine, the secretion of thyrotropin caused by thyroliberin.
Unlike somatostatin, octreotide suppresses the secretion of GH to a greater extent than the secretion of insulin, 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 patients with acromegaly, the use of the octreotide depot form ensures the maintenance of stable therapeutic concentrations of octreotide in the serum when the drug is administered once every 4 weeks. The introduction of octreotide depot form provides in the vast majority of cases a persistent decrease in the level of GR in serum and normalization of the concentration of insulin-like growth factor-1 (IGF-1) in serum.
In most patients with acromegaly, the octreotide depot significantly reduces the severity of symptoms such as headache, excessive sweating, paresthesia, tiredness, pain in bones and joints, carpal tunnel syndrome. In individual clinical cases, treatment with octreotide depot in patients with pituitary adenomas secreting GH resulted in a decrease in tumor size.
When secreting endocrine tumors of the gastrointestinal tract and pancreas, the use of the octreotide depot form provides constant monitoring of the main symptoms of these diseases.
Octreotide depot at a dose of 30 mg every 4 weeks slows down tumor growth in patients with secreting and non-secreting common (metastatic) neuroendocrine tumors of the skinny, ileum, blind, ascending colon, transverse colon, and worm-shaped appendix, or without metastasized neurodevelopment hearth. The drug significantly increased the time to progression in this category of patients: the median time to progression was 14.3 months compared to 6 months in the placebo group. After 6 months of treatment, stabilization was observed in 66% of patients in the octreotide depot group and 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.
In carcinoid 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 excretion of 5-hydroxyindoleacetic acid in the urine.
In tumors characterized by hyperproduction of a vasoactive intestinal peptide (VIPoma), the use of octreotide in most patients leads to a decrease in severe secretory diarrhea, which is characteristic of this condition, which, in turn, leads to an improvement in the patient’s quality of life. At the same time, there is a decrease in concomitant electrolyte imbalances, for example, hypokalemia, which allows you to cancel the enteral and parenteral administration of fluid and electrolytes. According to computed tomography, in some patients there is a slowdown or stop of tumor progression and even a decrease in its size, especially 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.
In glucagonomas, the use of octreotide in most cases leads to a significant decrease in necrolytic migratory erythema, which is typical for this condition. Octreotide does not have any significant effect on the severity of diabetes, 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 a decrease in it, which is accompanied by an increase in body weight. With the use of octreotide, a rapid decrease in the concentration of glucagon in the plasma is often noted, however, with prolonged treatment this effect is not saved. At the same time, the improvement of clinical symptoms persists for a long time.
In gastrinomas / Zollinger-Ellison syndrome, using octreotide as a monotherapy or in combination with histamine H2 receptor blockers and proton pump inhibitors, it is possible to reduce the formation of hydrochloric acid in the stomach and develop clinical improvement, including a decrease in the manifestations of diarrhea. It is also possible to reduce the severity and other symptoms, probably associated with the synthesis of peptides by the tumor, including tides. In some patients, a decrease in the concentration of gastrin in the plasma is noted.
In patients with insulinomas, octreotide decreases 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 improve without a simultaneous persistent decrease in blood insulin levels.
In patients with rare tumors that hyperproduce growth hormone releasing factor (somatoliberinomas), octreotide reduces the severity of acromegaly symptoms. This, apparently, is associated with suppression of the secretion of releasing factor of growth hormone and growth hormone itself. In the future, it is possible to reduce the size of the pituitary gland, which was increased before treatment.
Pharmacokinetics
After i / m administration of the octreotide depot, the concentration of octreotide in serum reaches a short initial peak within 1 h and then progressively decreases within 24 h until it reaches undetectable values. After the initial peak observed on the 1st day, the concentration of octreotide in the next 7 days in most patients remains within subtherapeutic values. After this, the concentration of octreotide increases again, reaches a plateau on about the 14th day and remains relatively constant over the next 3-4 weeks. The peak concentration on the first day is lower than the levels observed in the plateau phase. On the 1st day, no more than 0.5% of the total amount of active substance is released. After about 42 days, the concentration of octreotide slowly decreases, which occurs simultaneously with the final stage of degradation of the polymer matrix of the dosage form.
After the administration of octreotide depot form in a single dose of 10 mg, 20 mg and 30 mg octreotide concentrations in the plateau phase to patients with acromegaly, they were 358 ng / l, 926 ng / l and 1710 ng / l, respectively. Serum octreotide css achieved after 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals were 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 depot in doses of 10 mg, 20 mg and 30 mg with 4- what happens simultaneously with the final stage of degradation of the polymer matrix of the dosage form.
After the administration of octreotide depot form in a single dose of 10 mg, 20 mg and 30 mg octreotide concentrations in the plateau phase to patients with acromegaly, they were 358 ng / l, 926 ng / l and 1710 ng / l, respectively. Serum octreotide css achieved after 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals were 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 depot in doses of 10 mg, 20 mg and 30 mg with 4- what happens simultaneously with the final stage of degradation of the polymer matrix of the dosage form.
After the administration of octreotide depot form in a single dose of 10 mg, 20 mg and 30 mg octreotide concentrations in the plateau phase to patients with acromegaly, they were 358 ng / l, 926 ng / l and 1710 ng / l, respectively. Serum octreotide css achieved after 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals were 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 depot in doses of 10 mg, 20 mg and 30 mg with 4- 926 ng / l and 1710 ng / l, respectively. Serum octreotide css achieved after 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals were 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 depot in doses of 10 mg, 20 mg and 30 mg with 4- 926 ng / l and 1710 ng / l, respectively. Serum octreotide css achieved after 3 injections of Sandostatin LAR at doses of 20 mg and 30 mg at 4-week intervals were 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 depot in doses of 10 mg, 20 mg and 30 mg with 4-weekly intervals, the average serum Css values of 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), there was no cumulation of octreotide beyond that which could be expected due to partial overlap of the pharmacokinetic curves.
The pharmacokinetic profile of octreotide after injection of the octreotide depot forms 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 sc administration. Vd octreotide at equilibrium is 0.27 l / kg The total plasma clearance is 160 ml / min. Plasma protein binding is 65%. Octreotide does not bind to blood cells.
Indications
Treatment of acromegaly in the following cases: when adequate control of the manifestations of the disease is carried out by sc administration of Sandostatin
in the absence of a sufficient effect or with the complete ineffectiveness of surgical treatment or radiation therapy, and also after radiation therapy as a short-term treatment until its effect is fully developed.
Treatment of patients with symptoms of endocrine tumors of the gastrointestinal tract and pancreas when sc administration of Sandostatin provides adequate control of the manifestations of the disease: carcinoid tumors with manifestations of the carcinoid syndrome
VIPoma
glucagonoma
gastrinoma syndrome of pre-operative syndrome as well as for maintenance therapy of
somatoliberinomas (tumors characterized by overproduction of growth hormone releasing factor).
Treatment of patients with secreting and non-secreting common (metastatic) neuroendocrine tumors of the lean, ileum, blind, ascending colon, transverse colon, appendix, or metastases of neuroendocrine tumors without a primary lesion.
Pregnancy and lactation
The use of octreotide during pregnancy has not been studied. There is limited experience in the use of the drug in pregnant patients with acromegaly in clinical practice (in half the cases, the outcome of pregnancy was not known).
Most pregnant patients received octreotide therapy in the first trimester of pregnancy (in the form of Sandostatin 100-300 Ñg / day s / c or Sandostatin ® LAR 20-30 mg per month). In approximately 70% of cases with a known outcome, patients independently decided to continue therapy with the drug during pregnancy. In most patients (cases with a known outcome), the pregnancy ended in the birth of healthy children, however, several spontaneous abortions in the first trimester and cases of artificial termination of pregnancy were also reported.
When using octreotide during pregnancy, there were no cases of the development of congenital malformations in children.
Pregnant women are prescribed the drug only in cases of emergency.
In experimental studies, octreotide did not have a direct or indirect negative effect on pregnancy, the formation and maturation of the fetus, childbirth, and postnatal development, with the exception of temporary growth retardation.
It is not known whether octreotide with breast milk is excreted in humans. In experimental studies, the allocation of the drug with breast milk was noted.
If you need to use the drug during lactation, breastfeeding should be discontinued.
Composition of
1 bottle contains:
Active substances: octreotide acetate 33.6 mg, which corresponds to an octreotide content of 30 mg.
Excipients: lactic and glycolic acid copolymer – 566.4 mg, mannitol – 122.9 mg.
Solvent: sodium carmellose (sodium carboxymethyl cellulose) – 12.5 mg, mannitol – 15 mg, water d / i – up to 2.5 ml.
Dosage and administration of
Sandostatin ® LAR should only be injected deep into the buttock muscle. With repeated injections, the left and right sides should be alternated.
Acromegaly
For patients in whom the SC administration of Sandostatin ® provides adequate control of the disease, the recommended initial dose of Sandostatin ® LAR is 20 mg every 4 weeks for 3 months. You can start treatment with Sandostatin LAR on the day after the last s / c administration of Sandostatin. In the future, the dose is corrected taking into account the concentration in the serum of GR 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 GR 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 GR and IRF-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 there is a persistent decrease in serum concentration of GH below 1 μg / L, normalization of the concentration of IGF 1 and the disappearance of reversible symptoms of acromegaly, you can reduce the dose of Sandostatin ® LAR to 10 mg every 4 weeks. However, in these patients, receiving a relatively small dose of Sandostatin ® LAR, it is necessary to continue to carefully monitor serum concentrations of GR and IGF 1, as well as the symptoms of the disease.
In patients receiving a stable dose of Sandostatin ® LAR, the 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 even ineffective, as well as for patients who need short-term treatment after a course of radiation therapy until the development of its full effect, it is recommended to conduct a short trial course of treatment with s / to Sandostatin injections in order to assessment of its effectiveness and general tolerance, and only after that switch to the use of the drug 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 the manifestations of the disease, the recommended initial dose of the drug Sandostatin ® LAR is 20 mg every 4 weeks. SC administration of the drug Sandostatin ® should be continued for another 2 weeks after the first administration of the drug Sandostatin ® LAR.
For patients who have not previously received treatment with Sandostatin, it is recommended to start treatment with s / c 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 general tolerance. Only after this, Sandostatin ® LAR is prescribed according to the above scheme.
In case when Sandostatin ® LAR therapy for 3 months provides adequate control of the clinical manifestations and biological markers of the disease, you can reduce the dose of Sandostatin ® LAR to 10 mg every 4 weeks.
In cases where after 3 months of treatment with Sandostatin LAR only partial control of symptoms has been achieved, the dose can be increased to 30 mg every 4 weeks.
Against the background of treatment with Sandostatin ® LAR on certain days, it is possible to 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 concentrations of octreotide in plasma have been reached. In these cases, an additional s / c administration of Sandostatin in the dose used before starting treatment with Sandostatin LAR is recommended.
Secreting and non-secreting common (metastatic) neuroendocrine tumors of the skinny, ileum, blind, ascending colon, transverse colon, and appendix, or metastases of neuroendocrine tumors without an initially identified
lesion, the recommended dose of Sandardine ® is 30 mg every week. Sandostatin ® LAR therapy should be continued until signs of tumor progression.
Impaired renal function does not affect octreotide AUC. When using the drug Sandostatin ® LAR in patients with impaired renal function, dose adjustment is not required.
Impaired liver function. The results of a study in which s / c and iv administration of Sandostatin were used showed that a slowdown in the elimination of the drug can occur in patients with cirrhosis of the liver, however, in patients with fatty hepatosis this is not observed. Due to the wide therapeutic range of octreotide, there is no need to correct the dosage regimen of Sandostatin ® LAR in patients with cirrhosis.
The results of a study in which Sandostatin was administered sc to patients 65 years of age and older showed that there is no need to change the dosage regimen for the drug in elderly patients. Similarly, in this category of patients it is not necessary to adjust the dose of Sandostatin ® LAR.
Rules for the preparation of suspension for injection and in which Sandostatin was administered s / c to patients aged 65 years and older, showed that there is no need to change the dosage regimen to the drug for elderly patients. Similarly, in this category of patients it is not necessary to adjust the dose of Sandostatin ® LAR.
Rules for the preparation of suspension for injection and in which Sandostatin was administered s / c to patients aged 65 years and older, showed that there is no need to change the dosage regimen to the drug for elderly patients. Similarly, in this category of patients it is not necessary to adjust the dose of Sandostatin ® LAR.
Rules for the preparation of suspension for injection andadministration of
The following recommendations should be strictly observed. Introduce only a homogeneous suspension. Sandostatin ® LAR suspension is prepared immediately before administration. Sandostatin ® LAR should be prepared and administered only by specially trained medical personnel.
Incubate a bottle of Sandostatin LAR powder and a syringe with solvent at room temperature. Remove the cap from the vial containing Sandostatin ® LAR. Tapping the bottle lightly should ensure that the powder is evenly distributed along the bottom of the bottle. The bottle should be kept strictly upright.
Remove tip from solvent syringe. Place the attached needle on the syringe.
Sanitize a rubber stopper of a bottle with an alcohol swab. Insert the needle into the bottle with Sandostatin LAR by piercing the center of the rubber stopper. Without touching the contents of the vial with a needle, Carefully inject the solvent along the inside of the vial. Do not spray solvent directly into the powder. Remove the syringe from the vial.
It is essential that the vial remains stationary until the solvent contained in the vial is completely saturated with the suspension to form a suspension. After the solvent has completely impregnated the powder (in about 2-5 minutes) without turning the bottle over, check for the presence of dry powder at the walls and bottom of the bottle. If residues of dry powder are found, leave the bottle until completely saturated. At this time, the patient should be prepared for injection.
After verifying that there are no dry powder residues, the vial should be carefully rotated for 30-60 seconds until a uniform suspension is formed. The bottle should not be shaken, this can lead to loss of flakes and unsuitability of the suspension.
Quickly insert the needle through the rubber stopper into the vial. Then, lowering the needle slice down and tilting the vial at an angle of 45 °, slowly draw the suspension into the syringe completely. You can not turn the bottle over when filling the syringe – this may affect the sampled amount. Some small amount of suspension may remain on the walls and bottom of the vial. This is a normal phenomenon, the flow rate for the residue on the walls and bottom of the bottle is taken into account.
Change the needle immediately on the syringe (second needle from the package).
Suspension should be administered immediately after preparation. Gently flip the syringe to achieve a uniform suspension. Remove air from the syringe. Disinfect the injection site with an alcohol swab. Insert the needle deep into the gluteus maximus muscle then pull the syringe plunger back slightly to make sure that there is no damage to the vessel. Introduce the IM suspension slowly with constant pressure on the syringe plunger. When plugging the needle, replace it with another needle of the same diameter.
Sandostatin ® LAR should be injected deep into the gluteus maximus. You can not enter iv. If it enters a blood vessel, the needle and injection site should be changed.
Side effects
The main side effects were observed from the digestive, nervous, hepatobiliary systems, as well as metabolic disorders and the development of nutritional deficiency.
In clinical trials, the most frequently observed diarrhea, abdominal pain, nausea, bloating, headache, gallstones, hyperglycemia and constipation often – dizziness, pain of various localization, impaired bile colloid stability (cholesterol microcrystal formation), disorders thyroid function (lowering of TSH levels, total and free thyroxine), soft stool consistency, decreased glucose tolerance, vomiting, asthenia and hypoglycemia in rare cases – phenomena, reminiscent of acute intestinal obstruction – progressive bloating, severe pain in the epigastric region, tension of the abdominal wall, muscle protection.
Although the excretion of fat with feces may increase, there is still no evidence that prolonged treatment with octreotide can lead to nutritional deficiency due to malabsorption (malabsorption).
Very rare cases of acute pancreatitis have been reported that developed in the first hours or days of sc administration of octreotide (Sandostatin) and disappeared after discontinuation of the drug. In addition, with prolonged use of octreotide (Sandostatin) s / c, there have been cases of pancreatitis associated with cholelithiasis.
According to an ECG study, with the use of the drug in patients with acromegaly and carcinoid syndrome, an extension of the QT interval was observed, deviation of the electrical axis of the heart, early repolarization, low-voltage type of ECG, displacement of the transition zone, early P wave and nonspecific changes in the ST segment and T wave. Since this category of patients has heart disease, a causal relationship between the use of octreotide and the development of these adverse events does not installed.
Determining the incidence of adverse reactions in clinical trials: very often ( 1/10)
often ( 1/100, <1/10) sometimes ( 1/1000, <1/100) rarely ( 1/10 000, <1/1000) is very rare (<1/10 000), including single messages. From the digestive system: very often – diarrhea, abdominal pain, nausea, constipation, flatulence, cholelithiasis often – dyspepsia, vomiting, feeling of fullness / heaviness of the abdomen, steatorrhea, mild stool consistency, discoloration of the stool, anorexia, cholecystitis, impaired colloidal stability of bile (formation of microcrystals of cholesterol), hyperbilirubinemia, increased activity of hepatic transaminases. From the nervous system: very often – headache often – dizziness. From the endocrine system: very often – hyperglycemia often – hypothyroidism / thyroid dysfunction (decreased TSH, total and free thyroxine), hypoglycemia, impaired glucose tolerance. Dermatological reactions: often – itching, rash, hair loss. From the respiratory system: often – shortness of breath. From the cardiovascular system: often – bradycardia sometimes – tachycardia. Local reactions: very often – pain at the injection site. Others: sometimes – dehydration. Following therapy with octreotide in clinical practice, the following adverse events were noted, regardless of the presence of a causal relationship with the use of the drug. Allergic reactions: anaphylactic reactions, hypersensitivity. Dermatological reactions: urticaria. From the digestive system: acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice, increased activity of alkaline phosphatase, GGT. From the cardiovascular system: arrhythmias. Drug Interaction Octreotide decreases the 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 is some literature suggesting that somatostatin analogues may reduce the metabolic clearance of substances metabolized by the involvement of cytochrome P450 isoenzymes, which may be caused by GH suppression. As it cannot be ruled out that octreotide may also have this effect, caution should be exercised when prescribing, metabolised by the CYP3A4 isoenzyme and having a narrow range of therapeutic concentrations (eg, quinidine, terfenadine). Overdose Cases of overdose of Sandostatin ® LAR have been reported in doses of 100 mg to 163 mg per month. In these cases, the only undesirable phenomenon was the development of hyperemia. When using Sandostatin LAR at a dose of 60 mg per month to 90 mg every 2 weeks in patients with malignant neoplasms, the drug was generally well tolerated, but the following undesirable effects were noted: frequent urination, increased fatigue, depression, anxiety and decrease. Storage conditions Keep out of the reach of children, protected from light at a temperature of 2 ° to 8 ° C (in the refrigerator). On the day of injection, the vial with the drug and the ampoule with the solvent can be kept at a temperature below 25 ° C. Expiration 3 years. Deystvuyuschee substances Octreotide Terms of delivery from pharmacies Prescription Dosage form dosage form suspension for injection Sandoz GmbH, Switzerland
