Active ingredients: Octreotide
Sandostatin LAR 10 mg / 2.5 ml powder and solvent for suspension for injection
Sandostatin LAR 20 mg / 2.5 ml powder and solvent for suspension for injection
Sandostatin LAR 30 mg / 2.5 ml powder and solvent for suspension for injection
Sandostatin package inserts are available for pack sizes: - Sandostatin LAR 10 mg / 2.5 ml powder and solvent for suspension for injection, Sandostatin LAR 20 mg / 2.5 ml powder and solvent for suspension for injection, Sandostatin LAR 30 mg / 2.5 ml powder and solvent for suspension for injection
- Sandostatin 0.05 mg / ml solution for injection or concentrate for solution for infusion, Sandostatin 0.1 mg / ml solution for injection or concentrate for solution for infusion, Sandostatin 0.5 mg / ml solution for injection or concentrate for solution for infusion, Sandostatin 1 mg / 5 ml solution for injection or concentrate for solution for infusion
Why is Sandostatin used? What is it for?
Sandostatin is a synthetic somatostatin analogue compound. Somatostatin is normally present in the human body, where it inhibits the release of certain hormones such as growth hormone. The advantages of Sandostatin over somatostatin are that it is more potent and its action lasts longer.
Sandostatin LAR is used
- to treat acromegaly,
Acromegaly is a condition in which the body produces too much growth hormone. Normally, growth hormone controls the growth of tissues, organs and bones. When it is present in excessive quantities, it causes an increase in the size of bones and tissues, especially of the hands and feet. Sandostatin LAR greatly reduces the symptoms of acromegaly, which include headache, excessive sweating, numbness of the hands and feet, fatigue and joint pain. In most cases, the excessive production of growth hormone is caused by an enlargement of the pituitary gland (pituitary adenoma); Sandostatin LAR treatment can reduce the size of the adenoma.
Sandostatin LAR is used to treat people with acromegaly:
- when other types of treatment for acromegaly (surgery or radiotherapy) are unsuitable or have not worked;
- after radiotherapy, to cover the transition period until radiotherapy reaches maximum efficacy.
- to relieve symptoms associated with the excessive production of certain specific hormones and other related substances in the stomach, intestines and pancreas.
Excessive production of specific hormones and other related natural substances can be caused by some rare conditions of the stomach, intestines and pancreas. This situation alters the body's natural hormonal balance and results in a variety of symptoms, such as hot flashes, diarrhea, blood pressure, skin rashes and weight loss. Sandostatin LAR treatment helps control these symptoms.
- to treat neuroendocrine tumors located in the intestine (eg appendix, small intestine or colon).
Neuroendocrine tumors are rare cancers that can be found in different parts of the body. Sandostatin LAR is also used to control the growth of these tumors when they are located in the intestine (eg appendix, small intestine or colon).
- to treat pituitary adenomas that produce too much thyroid stimulating hormone (TSH)
Excessive amount of thyroid stimulating hormone (TSH) leads to hyperthyroidism. Sandostatin LAR is used to treat people with pituitary tumors that produce too much thyroid stimulating hormone (TSH):
- when other treatments (surgery or radiotherapy) are not indicated or have not been effective;
- after radiotherapy, to cover the period necessary for radiotherapy to reach maximum efficacy.
Contraindications When Sandostatin should not be used
Do not take Sandostatin:
- if you are allergic to octreotide or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Sandostatin
Talk to your doctor before taking Sandostatin LAR:
- if you know you have gallstones, or have had them in the past; tell your doctor, as prolonged use of Sandostatin LAR can lead to stone formation. Your doctor may ask you to have periodic checks of the gallbladder.
- if you know that you have problems with your blood sugar levels that are too high (diabetes) or too low (hypoglycaemia). When Sandostatin LAR is used to treat gastroesophageal variceal bleeding, blood sugar levels should be monitored.
- if you have previously had episodes of vitamin B12 deficiency, your doctor may ask you to periodically check your vitamin B12 levels.
Tests and checks
If you are receiving Sandostatin LAR treatment for a long time, your doctor may ask you to periodically check your thyroid function.
Your doctor will check your liver function.
Children
Experience with the use of Sandostatin LAR in children is limited.
Interactions Which drugs or foods can modify the effect of Sandostatin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. THE
You can generally continue to take other medicines while you are being treated with Sandostatin LAR. However, Sandostatin LAR has been reported to interact with some medications, such as cimetidine, cyclosporine, bromocriptine, quinidine and terfenadine.
If you are taking medicines to control blood pressure (such as beta blockers or calcium channel blockers) or agents to control the water and electrolyte balance, your doctor may decide to adjust your dosage.
If you are diabetic, your doctor may decide to adjust your insulin dosage.Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
Sandostatin LAR can only be used during pregnancy if clearly needed.
Patients of childbearing potential must use adequate contraception during treatment.
Patients should not breastfeed during treatment with Sandostatin LAR. It is not known whether Sandostatin LAR is excreted in human milk.
Driving and using machines
Sandostatin LAR has no or negligible influence on the ability to drive or use machines. However, some side effects such as headache and fatigue may occur during treatment with Sandostatin LAR which may reduce the ability to drive and use machines safely.
Dose, Method and Time of Administration How to use Sandostatin: Posology
Sandostatin LAR should always be administered as a deep gluteal injection. The site for repeated injections should be alternated between the left and right buttocks.
Overdose What to do if you have taken too much Sandostatin
If you take more Sandostatin LAR than you should
No life-threatening reactions have been reported after Sandostatin LAR overdose.
Symptoms of overdose are: flushing, frequent urination, fatigue, depression, anxiety and lack of concentration.
If you think you have symptoms of an overdose, tell your doctor right away.
If you forget to take Sandostatin LAR
If you forget the injection, it is recommended to give it as soon as you remember and then continue the therapy as usual. The delay of a few days in the administration is not harmful but could have a temporary reappearance of symptoms until they return to normal.
If you stop taking Sandostatin LAR
If treatment with Sandostatin LAR is stopped, symptoms may recur. Therefore, do not stop taking Sandostatin LAR unless your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Sandostatin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be serious. Tell your doctor right away if any of the following occur:
Very common (may affect more than 1 in 10 users):
- Gallstones that can cause sudden back pain.
- Elevated blood sugar levels.
Common (may affect up to 1 in 10 users):
- Decreased activity of the thyroid gland (hypothyroidism) with changes in heart rate, appetite or weight, tiredness, coldness or swelling in the front of the neck.
- Changes in thyroid function tests.
- Inflammation of the gallbladder (cholecystitis); Symptoms may include pain in the upper right abdomen, fever, nausea, yellowing of the skin and eyes (jaundice).
- Low blood sugar.
- Impaired glucose tolerance.
- Slow heartbeat.
Uncommon (may affect up to 1 in 100 users):
- Thirst, low urine output, dark urine, red and dry skin.
- Fast heartbeat.
Other serious side effects
- Hypersensitivity (allergy) reactions, including skin rash.
- A type of allergic reaction (anaphylaxis) which causes difficulty in breathing or dizziness.
- Inflammation of the pancreas (pancreatitis) symptoms may include sudden pain in the upper abdomen, nausea, vomiting, diarrhea.
- Inflammation of the liver (hepatitis); Symptoms may include yellowing of the skin and eyes (jaundice), nausea, vomiting, loss of appetite, generally feeling unwell, itching, lightly colored urine.
- Irregular heartbeat.
Tell your doctor immediately if you notice any of the side effects described above.
Other side effects:
Tell your doctor, pharmacist or nurse if you notice any of the side effects listed below. These are usually mild in intensity and tend to disappear with continued treatment.
Very common (may affect more than 1 in 10 users):
- Diarrhea.
- Abdominal pain.
- Nausea.
- Constipation.
- Flatulence.
- Headache.
- Local pain at the injection site.
Common (may affect up to 1 in 10 users):
- Upset stomach after eating (dyspepsia).
- He retched.
- Feeling of gastric fullness.
- Fatty stools.
- Soft stools.
- I made it clear.
- Dizziness
- Loss of appetite.
- Change in liver function tests.
- Hair loss
- Shortness of breath.
- Weakness.
If any of these side effects occur, please tell your doctor, nurse or pharmacist.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system. .agenziaitalianadelfarmaco.gov.it / it / responsible
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the package after "EXP". The expiry date refers to the last day of that month. Store the product between 2 ° and 8 ° C, protected from light. Sandostatin LAR can remain at room temperature on the day of administration.
However, the suspension should only be prepared immediately prior to intramuscular injection.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Sandostatin LAR contains
The active substance is octreotide acetate equal to octreotide as a free peptide ... 10 mg 20 mg 30 mg
The other ingredients are:
bottle: poly (DL lactide-co-glycolide), sterile mannitol.
solvent pre-filled syringe: carmellose sodium, mannitol, water for injections
Description of what Sandostatin LAR looks like and contents of the pack
Powder and solvent for suspension for injection. Extended-release formulation for intramuscular use.
Powder: white to off-white color.
Solvent: clear and colorless solution.
One pack contains: a bottle containing 10 mg, 20 mg or 30 mg octreotide microspheres, 1 pre-filled syringe of 2.5 ml of solvent to be used to suspend the powder and 2 needles (40 mm x 1.1 mm).
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LAR SANDOSTATIN POWDER AND SOLVENT FOR INJECTABLE SUSPENSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
A bottle contains:
Active principle
octreotide acetate equal to
octreotide as a free peptide ............................................. 10 mg ...... 20 mg ...... 30 mg
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Powder and solvent for suspension for injection.
Powder: white to off-white color.
Solvent: clear and colorless solution.
Extended-release formulation for intramuscular use.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of patients with acromegaly in whom surgery is inappropriate or ineffective, or waiting for radiotherapy to reach maximum efficacy (see section 4.2).
Treatment of patients with symptoms associated with functioning gastro-entero-pancreatic endocrine tumors such as carcinoid tumors with features of the carcinoid syndrome (see section 5.1).
Treatment of patients with advanced neuroendocrine tumors of the middle intestine or with unknown primary tumor location in which sites outside the middle intestine have been excluded.
Treatment of TSH-secreting pituitary adenomas:
• when the secretion does not normalize after surgery and / or radiotherapy;
• in patients in whom surgery is not appropriate;
• in irradiated patients, until radiotherapy reaches efficacy.
04.2 Posology and method of administration
Dosage
Acromegaly
It is recommended to start treatment with the administration of Sandostatin LAR 20 mg at 4-week intervals for 3 months. Patients on subcutaneous Sandostatin treatment can start Sandostatin LAR the day after the last dose of subcutaneous Sandostatin. Subsequent dose adjustments should be based on blood growth hormone (GH) and growth factor concentrations. insulin-like growth 1 / somatomedin C (IGF-1) and on clinical symptoms.
In patients in whom, within the 3-month period, both clinical symptoms and biochemical parameters (GH; IGF-1) have not been satisfactorily controlled (GH concentrations still higher than 2.5 mcg / L), the dose can be increased to 30 mg every 4 weeks. If after 3 months, GH, IGF-1, and / or symptoms are still not adequately controlled at the 30 mg dose, the dose can be increased to 40 mg every 4 weeks.
In patients where GH concentrations remain constantly below 1 microgram / L, serum IGF 1 concentrations normalize and most of the reversible signs / symptoms of acromegaly disappear after 3 months of treatment with 20 mg, Sandostatin LAR 10 mg may be administered every 4 weeks However, particularly in this patient group using this low dose Sandostatin LAR, adequate monitoring of serum GH and IGF-1 concentrations and signs and clinical symptoms.
In patients with a stable dose of Sandostatin LAR, GH and IGF 1 checks should be performed every 6 months.
Gastro-entero-pancreatic endocrine tumors
Treatment of patients with symptoms associated with functioning gastro-entero-pancreatic neuroendocrine tumors
It is recommended to initiate treatment with the administration of Sandostatin LAR 20 mg at 4-week intervals. Patients receiving subcutaneous Sandostatin should continue treatment at the previously effective dose for 2 weeks after the first injection of Sandostatin LAR.
In patients in whom both clinical symptoms and biochemical parameters are well controlled after 3 months of treatment, the dose can be reduced to Sandostatin LAR 10 mg every 4 weeks.
In patients in whom both clinical symptoms and biochemical parameters are only partially controlled after 3 months of treatment, the dose can be increased to Sandostatin LAR 30 mg every 4 weeks.
On days when symptoms associated with gastro-entero-pancreatic tumors worsen during treatment with Sandostatin LAR, additional administration of Sandostatin subcutaneously at the dose used prior to initiation of Sandostatin LAR is recommended. it can occur mainly in the first 2 months of treatment until therapeutic concentrations of octreotide are reached.
Treatment of patients with advanced neuroendocrine tumors of the middle intestine or with unknown primary tumor location in which sites outside the middle intestine have been excluded
The recommended dose of Sandostatin LAR is 30 mg administered every 4 weeks (see section 5.1). Sandostatin LAR treatment for tumor control should be continued even in the absence of tumor progression.
Treatment of TSH-secreting pituitary adenomas.
Sandostatin LAR treatment should be initiated at a dose of 20 mg at 4-week intervals for 3 months before considering a dose adjustment. The dose will then be adjusted on the basis of the TSH and thyroid hormone response.
Use in patients with impaired renal function
Impaired renal function does not change the total octreotide exposure (AUC) when administered subcutaneously as Sandostatin. Consequently, there is no need to adjust the dose of Sandostatin LAR.
Use in patients with impaired hepatic function
In a study in which Sandostatin was administered both subcutaneously and intravenously, it was found that the drug's elimination capacity may be reduced in patients with liver cirrhosis, but not in those with hepatic steatosis. In some cases, dosage adjustment may be required in patients with impaired hepatic function.
Use in elderly patients
In a study with Sandostatin administered subcutaneously, no dosage adjustment was required in subjects ≥65 years of age. Consequently, no dosage modification of Sandostatin LAR is required in this patient group.
Use in children
Experience with the use of Sandostatin LAR in children is limited.
Method of administration
Sandostatin LAR can only be administered as deep intramuscular injections. The site for repeated intramuscular injections should be alternated between the left and right buttocks (see section 6.6).
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
General
Since GH-secreting pituitary tumors can sometimes expand causing serious complications (eg visual field changes), careful monitoring of all patients is essential. In case of tumor expansion, the possibility of alternative procedures should be considered.
In acromegalic female patients, the therapeutic benefits of decreased growth hormone (GH) levels and normalization of insulin-like growth factor 1 (IGF-1) can potentially restore fertility. Female patients of childbearing potential should be advise to use "adequate contraception" during treatment with octreotide if necessary (see also section 4.6).
Thyroid function should be monitored in patients on prolonged treatment with octreotide.
Liver function should be monitored during octreotide therapy
Events related to the cardiovascular system
Common cases of bradycardia have been reported. Dosage adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control water and electrolyte balance may be necessary (see section 4.5).
Gallbladder and related events
Octreotide inhibits the secretion of cholecystokinin, resulting in reduced contractility of the gallbladder and an increased risk of sand and stone formation. The development of gallstones has been reported in 15 - 30% of patients on long-term treatment with Sandostatin for subcutaneous route. The prevalence in the general population (aged 40 to 60 years) is approximately 5 - 20%. Data on long-term exposure of patients with acromegaly or gastro-entero-pancreatic tumors to Sandostatin LAR suggest that treatment with Sandostatin LAR does not increase the incidence of gallstones compared to subcutaneous treatment. An ultrasound check of the gallbladder is however advisable both before and at 6-month intervals during treatment with Sandostatin LAR. If present, gallstones are generally asymptomatic; if they are symptomatic, they can be treated by dissolution with bile acids or with chir intervention urgent.
Carbohydrate metabolism
For its inhibitory action on growth hormone, glucagon and insulin release, Sandostatin LAR
it can affect the regulation of glucose metabolism. Postprandial glucose tolerance can be impaired. As reported in patients treated with subcutaneous Sandostatin, a state of persistent hyperglycaemia may be induced in some cases as a consequence of chronic administration of the drug. Hypoglycemia has also been reported.
In patients with concomitant Type I diabetes mellitus, Sandostatin LAR is likely to affect glucose regulation, and insulin requirements may be reduced. In non-diabetic patients and in patients with Type II diabetes with partially intact insulin reserves, subcutaneous administration of Sandostatin may result in an increase in postprandial blood glucose. It is therefore recommended to monitor glucose tolerance and antidiabetic therapy.
In patients with insulinoma, because octreotide has a greater relative potency of inhibition of growth hormone and glucagon secretion than insulin, and because the duration of the inhibitory effect on insulin is shorter, octreotide may increase the severity and prolong the duration of hypoglycaemia. These patients should be monitored closely.
Nutrition
In some patients, octreotide can impair the absorption of fat from the diet.
A consistent decrease in vitamin B12 levels and abnormal Schilling test results have been observed in some patients receiving octreotide. Monitoring of vitamin B12 levels is recommended during Sandostatin LAR therapy in patients who have previously had episodes of vitamin B12 deficiency.
04.5 Interactions with other medicinal products and other forms of interaction
Dosage adjustment of drugs such as beta-blockers, calcium channel blockers, or fluid and electrolyte control agents may be required when Sandostatin LAR is coadministered (see section 4.4).
Dosage adjustment of insulin and antidiabetic drugs may be required when Sandostatin LAR is co-administered (see section 4.4).
Octreotide has been shown to reduce intestinal absorption of cyclosporine and delay that of cimetidine.
Co-administration of octreotide and bromocriptine increases the bioavailability of bromocriptine.
Limited published data indicate that somatostatin analogues may decrease the metabolic clearance of compounds known to be metabolised by cytochrome P450 enzymes, due to growth hormone suppression. As it cannot be excluded that octreotide has this effect, it must therefore be caution in the use of other drugs mainly metabolised by CYP3A4 and which have a low therapeutic index (eg quinidine, terfenadine).
04.6 Pregnancy and lactation
Pregnancy
There are limited data on the use of octretotide in pregnant women (less than 300 exposed pregnancies) and in about one third of cases the pregnancy outcomes are unknown. Most of the reports were received after marketing of octreotide and over 50% of exposed pregnancies have been reported in acromegalic patients. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100 to 1200 mcg / day of Sandostatin administered subcutaneously or 10 to 40 mg / month of Sandostatin LAR. Congenital anomalies have been reported in about 4% of pregnancies with known outcome. For these cases a causal relationship with octreotide has not been suspected.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid using Sandostatin LAR during pregnancy (see section 4.4).
Feeding time
It is not known whether octreotide is excreted in human milk. Animal studies have shown that octreotide is excreted in human milk. Patients should not breastfeed during treatment with Sandostatin LAR.
Fertility
It is not known whether octreotide has an effect on human fertility. In males born to mothers treated during pregnancy and lactation, a delay in the descent of the testes was observed. Octreotide however did not impair fertility in male and female rats at doses up to 1 mg / kg body weight per day ( see paragraph 5.3)
04.7 Effects on ability to drive and use machines
Sandostatin LAR has no or negligible influence on the ability to drive or use machines. Patients should be advised to use caution when driving or operating machinery if they experience dizziness, asthenia / fatigue or headache while taking Sandostatin LAR.
04.8 Undesirable effects
Summary of the safety profile
The most frequently reported adverse reactions during octreotide therapy include gastrointestinal disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutrition disorders.
The most commonly reported adverse reactions during clinical trials with octreotide were diarrhea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and constipation. Other commonly reported adverse reactions were dizziness, localized pain, biliary sand, thyroid dysfunction (decreased thyroid hormone [TSH], decreased total T4 and free T4), loose stools, impaired glucose tolerance, vomiting, asthenia and hypoglycemia. .
Table of adverse reactions
The following adverse drug reactions, listed in Table 1, were collected during clinical studies with octreotide:
Adverse drug reactions (Table 1) are listed by frequency category, with the most frequent reaction first, using the following convention: very common (≥1 / 10); common (≥1 / 100,
Table 1 Adverse drug reactions reported in clinical studies
The spontaneously reported adverse drug reactions presented in Table 2 have been reported on a voluntary basis and it is not always possible to reliably determine frequency or a causal relationship to drug exposure.
Table 2 Adverse drug reactions from spontaneous reports
Description of selected adverse reactions
Gastrointestinal disorders
In rare cases, adverse events affecting the gastrointestinal tract may present the characteristics of an acute intestinal obstruction, with progressive abdominal distension, severe pain in the epigastric area, abdominal pain and abdominal defense reaction.
The frequency of gastrointestinal side effects is known to decrease over time with continued treatment.
Injection site reactions
Injection site related reactions including pain, burning, redness, hematoma, haemorrhage, itching or swelling have been commonly reported in patients receiving Sandostatin LAR; however these events did not require any clinical intervention in most cases.
Metabolism and nutrition disorders
Although measured excretion of faecal fat may be increased, there is however no evidence to date that long-term treatment with octreotide has caused a nutritional deficiency from malabsorption.
Pancreatic enzymes
In very rare cases, acute pancreatitis has been reported within the first hours or days of subcutaneous Sandostatin treatment and resolved on discontinuation of the drug. In addition, cholelithiasis-induced pancreatitis has been reported in patients on long-term treatment with subcutaneous Sandostatin.
Cardiac pathologies
Electrocardiographic changes such as QT prolongation, axial deviation, early repolarization, low voltage, R / S transition, early R-wave progression and non-specific ST-wave changes have been observed in both patients with acromegaly and patients with carcinoid syndrome. T. The relationship between these events and octreotide acetate treatment has not been established as many of these patients have underlying heart disease (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address: http://www.agenziafarmaco.gov.it/it/responsabili
04.9 Overdose
A limited number of cases of accidental overdose of Sandostatin LAR have been reported. Doses ranged from 100 mg to 163 mg / month of Sandostatin LAR. The only adverse event reported was hot flashes.
Cancer patients have been reported receiving Sandostatin LAR doses of up to 60 mg / month and up to 90 mg / 2 weeks. These dosages were usually well tolerated, however the following side effects have been reported: frequent urination, fatigue, depression, anxiety and lack of concentration.
Treatment in the event of an overdose is symptomatic.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Somatostatin and analogues, ATC code: H01CB02
Octreotide is a synthetic octapeptide, structural analogue of natural somatostatin with pharmacological activity completely similar to the endogenous hormone, but with a considerably longer duration of action. It inhibits the pathological increase in the secretion of growth hormone (GH) and peptides and serotonin produced in the gastro-entero-pancreatic endocrine system (GEP).
In animals, octreotide has been shown to be a more potent GH, glucacone and insulin release inhibitor than somatostatin, with more marked selectivity for GH and glucagon suppression.
In healthy subjects, octreotide, like somatostatin, has been shown to inhibit:
• arginine-induced GH release, exercise and insulin-induced hypoglycemia,
• the post-prandial release of insulin, glucagon, gastrin, other peptides of the endocrine system GEP and the release of insulin and glucacone induced by arginine,
• the release of TSH (thyrotropic hormone) induced by the hormone TRH (hormone that releases thyrotropin).
Unlike somatostatin, octreotide is more potent in inhibiting GH secretion than insulin; its administration is not followed by rebound hypersecretion of hormones (eg GH in patients with acromegaly).
In patients with acromegaly, Sandostatin LAR, a galenic formulation of octreotide suitable for repeated administration at 4-week intervals, releases constant and therapeutic serum octreotide concentrations thereby consistently lowering GH and normalizing serum IGF-1 concentrations in most of the patients. In most patients, Sandostatin LAR greatly reduces the clinical symptoms of the disease, such as headache, excessive perspiration, paraesthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In previously untreated acromegalic patients with GH-secreting pituitary adenoma, treatment with Sandostatin LAR resulted in> 20% tumor volume reduction in a significant proportion (50%) of patients.
In patients with GH-secreting pituitary adenoma, Sandostatin LAR has been observed to cause tumor shrinkage (prior to surgery). However, surgery should not be delayed.
In patients with functioning tumors of the gastro-entero-pancreatic endocrine system, treatment with Sandostatin LAR ensures continuous control of disease-related symptoms. The effects of octreotide on the different types of gastro-entero-pancreatic tumors are as follows:
Carcinoid tumors
Administration of octreotide may result in improvement of symptoms particularly of hot flashes and diarrhea. In many cases, this is accompanied by a decrease in plasma serotonin and a decrease in urinary excretion of 5-hydroxyindolacetic acid.
VIPomi
The biochemical characteristics of these tumors consist in the overproduction of vasoactive intestinal peptide (VIP). In most cases, the administration of octreotide results in an "attenuation of the typical severe secretory diarrhea characteristic of this condition, with consequent improvement in the quality of life. This is accompanied by an improvement in associated electrolyte abnormalities, such as hypokalaemia," allowing the suspension of enteral and parenteral electrolyte fluid nutrition. In some patients, computed tomography shows a decrease or arrest of tumor progression, or even reduction of tumor progression, particularly liver metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which can reach normal values.
Glucagonomes
Administration of octreotide results in a substantial improvement in the necrolytic migratory rash which is characteristic of this condition in most cases. The effect of octreotide on the conditions of mild diabetes mellitus which often occurs is not marked and generally does not result in decreased doses of insulin or oral hypoglycemic agents. Octreotide results in improvement of diarrhea, and therefore weight gain in patients with this condition. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.
Gastrinomas / Zollinger-Ellison Syndrome
Proton pump inhibitor or H2 receptor inhibitor therapy generally controls gastric acid hypersecretion. However, diarrhea, which is also a dominant symptom, may not be adequately relieved by proton pump inhibitors or H2 receptor inhibitors. Sandostatin LAR may help to further reduce gastric acid hypersecretion and improve symptoms, including diarrhea, by suppressing elevated gastrin levels in some patients.
Insulinomas
Administration of octreotide produces a decrease in plasma concentrations of immunoreactive insulin. In patients with operable tumors, octreotide helps restore and maintain normoglycemia at preoperative levels. In patients with inoperable benign or malignant tumors, glycemic control may be improved even without sustained concomitant reduction in circulating insulin levels.
Treatment of patients with advanced neuroendocrine tumors of the middle intestine or with unknown primary tumor location in which sites outside the middle intestine have been excluded
A Phase IIII, randomized, double-blind, placebo-controlled study (PROMID) demonstrated that Sandostatin LAR inhibits tumor growth in patients with advanced neuroendocrine tumors of the midgut.
85 patients were randomized to receive Sandostatin LAR 30 mg every 4 weeks (n = 42) or placebo (n = 43) for 18 months, until cancer progression or death.
The main inclusion criteria were: untreated (naive) patients; well-differentiated functioning or non-functioning, histologically confirmed, locally inoperable or metastatic neuroendocrine tumors / carcinomas
with primary tumor located in the middle intestine or of unknown origin but thought to have originated in the middle intestine if a primary tumor of the pancreas, chest or other site was excluded.
The primary endpoint was time to tumor progression or tumor-related death (TTP).
In the intent-to-treat (ITT) population analysis (all randomized patients), 26 and 41 cancer-related progressions or deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR = 0.32; 95% CI, 0.19 - 0.55; p-value = 0.000015).
In the conservative analysis of the ITT population (cITT) in which 3 patients were censored at randomization, 26 and 40 tumor-related progressions or deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR = 0.34; 95% CI, 0.20 - 0.59; p-value = 0.000072; Fig. 1).Median time to tumor progression was 14.3 months in the Sandostatin LAR group (95% CI, 11.0 - 28.8 months) and 6.0 months in the placebo group (95% CI, 3.7 - 9 ,4 months).
In the per-protocol (PP) population analysis in which other patients were censored at the end of study therapy, 19 and 38 tumor progression or tumor-related deaths were observed in the Sandostatin LAR and placebo groups, respectively (HR = 0, 24; 95% CI, 0.13-0.45; p-value = 0.0000036).
Table 3 Results of the TTP according to the population analysis
The treatment effect was similar in patients with functional (HR = 0.23; 95% CI, 0.09-0.57) and nonfunctioning (HR = 0.25; 95% CI, 0.10- 0.59).
After 6 months of treatment, disease stabilization was observed in 66% of patients in the Sandostatin LAR group and in 37% of patients in the placebo group.
Based on the significant clinical benefit of Sandostatin LAR observed in the planned interim analysis, enrollment was discontinued.
In this study, the tolerability profile of Sandostatin LAR matched its known tolerability profile.
Treatment of TSH-secreting pituitary adenomas
An intramuscular injection of Sandostatin LAR every 4 weeks has been shown to suppress elevated thyroid hormone levels leading to normalization of TSH and improvement of clinical signs and symptoms of hyperthyroidism in patients with TSH-secreting adenomas. Sandostatin LAR treatment reached statistical significance from baseline after 28 days and treatment benefit was maintained for up to 6 months.
05.2 "Pharmacokinetic properties
Following intramuscular administration of Sandostatin LAR, the serum concentration of octreotide reaches an initial transient peak within 1 hour after administration, followed by a progressive decrease in concentration to undetectable levels within 24 hours. After this peak on day 1, octreotide concentration remains at subtherapeutic levels for the next 7 days in most patients. Octreotide levels then rise again to plateau concentrations by day 14 and remain relatively stable over the next 3-4 weeks. The peak level during day 1 is below the levels of the plateau phase and no more than 0.5% of the drug is released during day 1. From the 42nd day, the octreotide concentration slowly decreases, concurrent with the phase. of final degradation of the polymer matrix of the pharmaceutical form.
In patients with acromegaly, the mean plateau concentrations of octreotide following single administrations of 10 mg, 20 mg, 30 mg of Sandostatin are approximately 358 ng / L, 926 ng / L and 1710 ng / L, respectively. Steady-state was achieved after 3 injections at 4-week intervals, and is higher by a factor of approximately 1.6 - 1.8 and corresponds to 1557 ng / L and 2384 ng / L after repeated injections of 20 - 30 mg of Sandostatin LAR respectively.
Mean (and median) steady-state serum octreotide concentrations in patients with carcinoid tumors increased linearly with administered dose and were found to be 1231 ng / L, 2620 ng / L and 3928 ng / L after repeated injections. 10 mg, 20 mg, and 30 mg of Sandostatin LAR, respectively, administered at 4-week intervals.
It was observed that up to 28 monthly Sandostatin LAR injections there was no accumulation of octreotide beyond that predicted by the overlapping of release profiles.
The pharmacokinetic profile of octreotide after Sandostatin LAR injections reflects the release profile from the polymer matrix and its biodegradation. After its release into the systemic circulation, octreotide is distributed according to its known pharmacokinetic properties as described for subcutaneous administration. The steady-state volume of distribution of octreotide is 0.27 L / kg, and the total body elimination is 160 ml / min. The plasma protein binding is 65%. The amount of octreotide bound to the cells blood is irrelevant.
Pharmacokinetic data obtained in a limited number of blood samples in pediatric patients aged 7-17 years, with hypothalamic obesity, receiving Sandostatin LAR 40 mg per month, showed mean minimum octreotide plasma concentrations of 1395 ng. / L after the first injection and 2973 ng / L at steady state. A high variability between subjects was observed.
Steady state trough octreotide concentrations were not correlated with age and BMI, but were moderately correlated with body weight (52.3-133 kg) and were significantly different between male and female patients, i.e. approximately 17% higher in female patients.
05.3 Preclinical safety data
Animal studies of acute and repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicity have shown no special hazard for humans.
Reproduction studies in animals revealed no evidence of teratogenic, embryo / fetal or other reproductive effects due to parenterally administered octreotide at doses up to 1 mg / kg / day. Some observed retardation in the physiological growth of rat offspring was transient and attributable to "GH inhibition due to" excessive pharmacodynamic activity (see section 4.6).
No specific studies have been conducted in juvenile rats. In pre- and postnatal development studies, reduced growth and maturation was observed in F1 offspring of mothers who received octreotide throughout pregnancy and lactation. Delayed descent was observed in male F1 offspring. testicles but the fertility of these male F1 puppies remained normal. Thus, the effects mentioned above were transient and considered a consequence of GH inhibition.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Bottle: Poly (DL lactide-co-glycolide), sterile mannitol.
Pre-filled syringe (solvent for parenteral use): Carmellose sodium, mannitol, water for injections.
06.2 Incompatibility
Sandostatin LAR microspheres for injection must be diluted only with the appropriate solvent and not
must be injected together with other products. Therefore compatibility with other drugs has not been evaluated.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Store the product between 2 ° and 8 ° C, protected from light. Sandostatin LAR can remain at room temperature on the day of administration.
However, the suspension should only be prepared immediately prior to intramuscular injection.
Sandostatin LAR must be kept out of the reach and sight of children.
06.5 Nature of the immediate packaging and contents of the package
One pack contains:
a bottle containing 10 mg, 20 mg or 30 mg octreotide microspheres, 1 pre-filled syringe of 2.5 ml of solvent to be used for the suspension of the powder and 2 needles (40 mm x 1.1 mm).
The microspheres are packaged in a 5 ml glass bottle, closed with a Teflon-coated rubber stopper and an aluminum cap with plastic protection.
The solvent is contained in a closed glass syringe with two rubber stoppers positioned on the front and on the plunger.
06.6 Instructions for use and handling
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
Instructions for intramuscular injection of Sandostatin LAR, to be administered only in the deep gluteal areaFollow the instructions below carefully to ensure complete saturation of the powder and formation of a uniform suspension prior to intramuscular administration.
The Sandostatin LAR suspension should only be prepared immediately prior to administration.
It is recommended that Sandostatin LAR be administered only by trained healthcare professionals.
Allow the bottle of Sandostatin LAR and the syringe with the solvent to reach room temperature.
Remove the protective cap from the bottle containing Sandostatin LAR. Gently tap the bottom of the bottle on a hard surface to settle all the powder at the bottom of the bottle.
Remove the protective cap from the syringe containing the solvent.
Insert one of the needles onto the syringe
Disinfect the rubber stopper of the bottle with an alcohol swab. Insert the needle into the center of the rubber stopper of the bottle containing Sandostatin LAR.
Slowly inject the solvent into the bottle, letting it run along the walls without moving the Sandostatin LAR powder. Do not directly inject the solvent into the powder. Remove the needle from the bottle.
Do not shake the bottle until the solvent has wetted all the Sandostatin LAR powder (after about 2-5 minutes).
Without turning the bottle upside down, check the powder on the sides and bottom of the bottle. If dry spots persist, let the solvent wet the powder, without shaking.
When the solvent has uniformly wetted all the powder, shake the bottle with moderate rotating movements, for about 30 - 60 seconds, until a uniform and cloudy suspension is obtained.
Do not shake the bottle excessively as this could cause flocculation of the suspension making it unusable.
Immediately reinsert the needle into the rubber stopper and, placing the bottle on a rigid surface at an angle of approximately 45 °, slowly draw the contents of the bottle into the syringe.
Do not turn the bottle upside down when filling the syringe as this may affect the amount drawn.
It is normal for a small amount of suspension to remain on the walls and bottom of the bottle. This is a calculated excess.
Immediately replace the used needle with the other one contained in the package.
The product should be administered immediately after preparation of the suspension. Slowly invert the syringe to maintain a uniform suspension. Remove the air from the syringe.
Disinfect the injection site with an alcohol swab. Slowly and with constant pressure, make a deep intramuscular injection into the right or left gluteal site, after aspirating to ensure that you are not in a venous vessel. If the needle becomes blocked, insert a new needle of the same diameter [1.1 mm, 19 gauge].
Sandostatin LAR should only be administered by the deep intramuscular route and never by the intravenous route.
In case of accidental involvement of a blood vessel, insert a new needle and change the injection site.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Farma S.p.A.
Largo Umberto Boccioni, 1 - 21040 Origgio (VA)
08.0 MARKETING AUTHORIZATION NUMBER
Sandostatin LAR 10 mg powder and solvent for suspension for injection
Powder bottle + 2,5 ml pre-filled syringe + 2 needles - A.I.C. n. 027083082
Sandostatin LAR 20 mg powder and solvent for suspension for injection
Powder bottle + 2.5 ml pre-filled syringe + 2 needles - AIC. n. 027083094
Sandostatin LAR 30 mg powder and solvent for suspension for injection
Powder bottle + 2,5 ml pre-filled syringe + 2 needles - A.I.C. n. 027083106
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
First authorization: 19.09.1995
Renewal: 01.06.2010
10.0 DATE OF REVISION OF THE TEXT
09/2015
