SANDOSTATIN 0.1 MGML

Israel - English - Ministry of Health

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Active ingredient:
OCTREOTIDE
Available from:
NOVARTIS ISRAEL LTD
ATC code:
H01CB02
Pharmaceutical form:
SOLUTION FOR INJECTION / INFUSION
Composition:
OCTREOTIDE 0.1 MG/ML
Administration route:
S.C, I.V
Prescription type:
Required
Manufactured by:
NOVARTIS PHARMA STEIN AG, SWITZERLAND
Therapeutic group:
OCTREOTIDE
Therapeutic area:
OCTREOTIDE
Therapeutic indications:
Prevention of complications following pancreatic surgery. Symptomatic control and reduction of GH and IGF-1plasma levels in patients with acromegaly who are inadequately controlled by surgery or radiotherapy. Sandostatin treatment is also indicated for acromegalic patients unfit or unwilling to undergo surgery or in the interim period until radiotherapy becomes fully effective. Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours: - Carcinoid tumours with features of the carcinoid syndrome - VIPomas - Glucagonomas - Gastrinomas / zollinger-Ellison syndrome usually in conjunction with proton pump inhibitors or H2- antagonist therapy - Insulinomas for pre-operative control of hypoglycaemia and for maintenance therapy - GRFomas. Sandostatin is not an antitumour therapy and is not curative in these patients.Emergency management of bleeding gastro-oesophageal varices secondary to cirrhosis in combination with specific therapy such as endoscopic sclerot
Authorization number:
047 01 25698 00
Authorization date:
2020-03-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Hebrew

05-10-2020

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ(

05.2013

:ךיראת

6.11.2014

.

:םושירה רפסמו תילגנאב רישכת םש

Sandostatin 0.05 mg 047-03-25697-00

Sandostain 0.1mg 047-01-25698-00

Sandostain 0.2mg 047-02-25699-00

Sandostatin 0.5mg 107-13-27200-00

:םושירה לעב םש

Novartis Pharma Services AG

.

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט תושקובמה תורמחהה

Warnings and

precautions

Cardiovascular related events

Uncommon cases of bradycardia have

been reported.

Cardiovascular related events

Uncommon cCases of bradycardia have

been reported (frequency: common).

Warnings and

precautions

Glucose metabolism

Glucose metabolism

… Hypoglycemia has also been reported.

Adverse

drug

reactions

Table 1 Adverse drug reactions reported

in clinical studies

….

General disorders and administration

site disorders:

Very common:

Injection site

localized pain

….

Table 7.1 Adverse drug reactions

reported in clinical studies

General disorders and administration

site conditions

Very common:

Injection

site

localized

pain

reaction.

Common:

Asthenia

8 Interactions

Dose adjustment of medicinal products

such as beta blockers, calcium channel

blockers, or agents to control fluid and

electrolyte balance may be necessary

when Sandostatin LAR is administered

concomitantly (see section 6 Warnings

and precautions).

Dose

adjustments

insulin

antidiabetic medicinal products may be

required

when

Sandostatin

administered concomitantly (see section

6 Warnings and precautions).

צמ

"

ןולעה ב

,

תונמוסמ ובש

תושקובמה תורמחהה בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב( םייוניש אלו יתוהמ ןכות קר ןמסל שי .הנוש עבצב .טסקטה םוקימב ךיראתב ינורטקלא ראודב רבעוה

6

,רבמבונב

2014

SAS API SEP20 V8

UK SmPC JAN20

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Sandostatin

0.05mg/ml

Sandostatin

0.1 mg/ ml

Sandostatin

0.5 mg/ml

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One ampoule of 1 ml contains 0.05, 0.1 or 0.5 mg octreotide (as octreotide acetate)

Excipient(s) with known effect

Contains less than 1 mmol (23 mg) sodium per dose, i.e. is essentially “sodium-free”.

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection /infusion.

Clear, colourless solution.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic Indications

Prevention of complications following pancreatic surgery.

Symptomatic control and reduction of growth hormone (GH) and IGF-1 plasma levels in patients with

acromegaly who are inadequately controlled by surgery or radiotherapy. Sandostatin treatment is also

indicated for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until

radiotherapy becomes fully effective.

Relief of symptoms associated with functional gastro-entero-pancreatic (GEP) endocrine tumors:

Carcinoid tumors with features of the carcinoid syndrome.

VIPomas.

Glucagonomas.

Gastrinomas/Zollinger-Ellison syndrome, usually in conjunction with proton pump inhibitors, or

H2-antagonist therapy.

Insulinomas, for pre-operative control of hypoglycemia and for maintenance therapy.

GRFomas.

Sandostatin is not an anti-tumors therapy and is not curative in these patients.

Emergency management of bleeding gastro-esophageal varices secondary to cirrhosis in combination

with specific therapy such as endoscopic sclerotherapy.

SAS API SEP20 V8

UK SmPC JAN20

4.2.

Posology and method of administration

Posology

General target population

Acromegaly

Initially 0.05 to 0.1 mg by subcutaneous (s.c.) injection every 8 or 12 hours. Dosage

adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH

<2.5 ng/mL; IGF-1 within normal range) and clinical symptoms, and on tolerability. In most

patients, the optimal daily dose will be 0.3 mg. A maximum dose of 1.5 mg per day should

not be exceeded. For patients on a stable dose of Sandostatin, assessment of GH should be

made every 6 months.

If no relevant reduction in GH levels and no improvement in clinical symptoms have been

achieved within 3 months of starting treatment with Sandostatin, therapy should be

discontinued.

Gastro-entero-pancreatic endocrine tumours

Initially 0.05 mg once or twice daily by s.c. injection. Depending on clinical response, effect

on levels of tumour-produced hormones (in cases of carcinoid tumours, on the urinary

excretion of 5-hydroxyindole acetic acid), and on tolerability, dosage can be gradually

increased to 0.1 to 0.2 mg 3 times daily. Under exceptional circumstances, higher doses may

be required. Maintenance doses have to be adjusted individually.

In carcinoid tumours, if there is no beneficial response within 1 week of treatment with

Sandostatin at the maximum tolerated dose, therapy should not be continued.

Complications following pancreatic surgery

0.1 mg 3 times daily by s.c. injection for 7 consecutive days, starting on the day of operation

at least 1 hour before laparotomy.

Bleeding gastro-oesophageal varices

25 micrograms/hour for 5 days by continuous intravenous (i.v.) infusion. Sandostatin can be

used in dilution with physiological saline.

In cirrhotic patients with bleeding gastro-oesophageal varices, Sandostatin has been well

tolerated at continuous i.v. doses of up to 50 micrograms/hour for 5 days.

Special populations

Geriatric Populations

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients

treated with Sandostatin.

Pediatric Population

Experience with Sandostatin in children is limited.

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UK SmPC JAN20

Hepatic impairment

In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating

adjustment of the maintenance dosage.

Renal impairment

Impaired renal function did not affect the total exposure (AUC) to octreotide administered as

s.c. injection, therefore no dose adjustment of Sandostatin is necessary.

Method of administration

Sandostatin may be administered directly by subcutaneous (s.c.) injection or by intravenous

(i.v.) infusion after dilution. For further instructions on handling and instructions for dilution

of the medicinal product, refer to section 6.6.

4.3.

Contraindications

Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications

(e.g. visual field defects), it is essential that all patients be carefully monitored. If evidence of

tumour expansion appears, alternative procedures may be advisable.

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of

insulin-like growth factor 1 (IGF-1) concentration in female acromegalic patients could

potentially restore fertility. Female patients of childbearing potential should be advised to use

adequate contraception if necessary during treatment with octreotide (see section 4.6).

Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.

Hepatic function should be monitored during octreotide therapy.

Cardiovascular related events

Common cases of bradycardia have been reported. Dose adjustments of medicinal products

such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte

balance, may be necessary (see section 4.5).

Gallbladder and related events

Cholelithiasis is a very common event during Sandostatin treatment and may be associated

with cholecystitis and biliary duct dilatation (see section 4.8).

Ultrasonic examination of the

gallbladder before, and at about 6- to 12-month intervals during Sandostatin therapy is

therefore recommended.

GEP endocrine tumours

During the treatment of GEP endocrine tumours, there may be rare instances of sudden escape

from symptomatic control by Sandostatin, with rapid recurrence of severe symptoms. If the

treatment is stopped, symptoms may worsen or recur.

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UK SmPC JAN20

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon, and insulin, Sandostatin may

affect glucose regulation. Post-prandial glucose tolerance may be impaired and, in some

instances, the state of persistent hyperglycaemia may be induced as a result of chronic

administration. Hypoglycaemia has also been reported.

In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting

the secretion of GH and glucagon than that of insulin, and because of the shorter duration of

its inhibitory action on insulin, may increase the depth and prolong the duration of

hypoglycaemia. These patients should be closely monitored during initiation of Sandostatin

therapy and at each change of dosage. Marked fluctuations in blood glucose concentration

may possibly be reduced by smaller, more frequently administered doses.

Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by

administration of Sandostatin. In non-diabetics and type II diabetics with partially intact

insulin reserves, Sandostatin administration can result in post-prandial increases in glycaemia.

It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.

Oesophageal varices

Since, following bleeding episodes from oesophageal varices, there is an increased risk for the

development of insulin-dependent diabetes or for changes in insulin requirement in patients

with pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.

Local Site Reactions

In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the s.c.

injection site only at the highest dose (about 8 times the maximum human dose based on body

surface area). No hyperplastic or neoplastic lesions occurred at the s.c. injection site in a 52-

week dog toxicity study. There have been no reports of tumour formation at the injection sites

in patients treated with Sandostatin for up to 15 years. All the information available at present

indicates that the findings in rats are species specific and have no significance for the use of

the drug in humans (see section 5.3).

Nutrition

Octreotide may alter absorption of dietary fats in some patients.

Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some

patients receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended

during therapy with Sandostatin in patients who have a history of vitamin B12 deprivation.

Sodium content

Sandostatin contains less than 1 mmol (23 mg) sodium per dose, i.e is essentially “sodium-

free”.

4.5

Interactions with other medicinal products and other forms of interaction

Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or

agents to control fluid and electrolyte balance may be necessary when Sandostatin is

administered concomitantly (see section 4.4).

Dose adjustments of insulin and antidiabetic medicinal products may be required when

Sandostatin is administered concomitantly (see section 4.4).

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UK SmPC JAN20

Sandostatin has been found to reduce the intestinal absorption of cyclosporin and to delay that

of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the bioavailability of

bromocriptine.

Limited published data indicate that somatostatin analogues might decrease the metabolic

clearance of compounds known to be metabolised by cytochrome P450 enzymes, which may

be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may

have this effect, other drugs mainly metabolised by CYP3A4 and which have a low

therapeutic index should therefore be used with caution (e.g. quinidine, terfenadine).

4.6.

Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of

octreotide in pregnant women, and in approximately one third of the cases the pregnancy

outcomes are unknown. The majority of reports were received after post-marketing use of

octreotide and more than 50% of exposed pregnancies were reported in patients with

acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy

at doses ranging from 100-1200 micrograms/day of Sandostatin s.c. or 10-40 mg/month of

Sandostatin LAR. Congenital anomalies were reported in about 4% of pregnancy cases for

which the outcome is known. No causal relationship to octreotide is suspected for these cases.

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 the use of Sandostatin during pregnancy

(see section 4.4).

Breastfeeding

It is unknown whether octreotide is excreted in human breast milk. Animal studies have

shown excretion of octreotide in breast milk. Patients should not breast-feed during

Sandostatin treatment.

Fertility

It is not known whether octreotide has an effect on human fertility. Late descent of the testes

was found for male offsprings of dam treated during pregnancy and lactation. Octreotide,

however, did not impair fertility in male and female rats at doses of up to 1 mg/kg body

weight per day (see section 5.3).

4.7.

Effects on ability to drive and use machines

Sandostatin has no or negligible influence on the ability to drive and use machines. Patients

should be advised to be cautious when driving or using machines if they experience dizziness,

asthenia/fatigue, or headache during treatment with Sandostatin.

4.8

Undesirable effects

Summary of the safety profile

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The most frequent adverse reactions reported during octreotide therapy include

gastrointestinal

disorders, nervous system disorders, hepatobiliary disorders, and metabolism

and nutritional disorders.

The most commonly reported adverse reactions in clinical trials with octreotide administration

were diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia

and constipation. Other commonly reported adverse reactions were dizziness, localised pain,

biliary sludge, thyroid dysfunction (e.g. decreased thyroid stimulating hormone [TSH],

decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting,

asthenia, and hypoglycaemia.

Tabulated list of adverse reactions

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical

studies with octreotide:

Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent

first, using the following convention: very common (

1/10); common (

1/100, < 1/10);

uncommon (

1/1,000, ≤ 1/100); rare (

1/10,000, ≤ 1/1,000) very rare (≤ 1/10,000),

including isolated reports. Within each frequency grouping, adverse reactions are ranked in

order of decreasing seriousness.

Table 1 Adverse drug reactions reported in clinical studies

Gastrointestinal disorders

Very common:

Diarrhoea, abdominal pain, nausea, constipation, flatulence.

Common:

Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose

stools, discolouration of faeces.

Nervous system disorders

Very common:

Headache.

Common:

Dizziness.

Endocrine disorders

Common:

Hypothyroidism, thyroid disorder (e.g. decreased TSH,

decreased total T4, and decreased free T4).

Hepatobiliary disorders

Very common:

Cholelithiasis.

Common:

Cholecystitis, biliary sludge, hyperbilirubinaemia.

Metabolism and nutrition disorders

Very common:

Hyperglycaemia.

Common:

Hypoglycaemia, impaired glucose tolerance, anorexia.

Uncommon:

Dehydration.

General disorders and administration site conditions

Very common:

Injection site reactions.

Common:

Asthenia.

Investigations

Common:

Elevated transaminase levels.

Skin and subcutaneous tissue disorders

Common:

Pruritus, rash, alopecia.

Respiratory disorders

Common:

Dyspnoea.

Cardiac disorders

Common:

Bradycardia

Uncommon:

Tachycardia.

Post-marketing

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Spontaneously reported

adverse reactions presented in Table 2, are reported voluntarily and it

is not always possible to reliably establish frequency or a causal relationship to drug exposure

.

Table 2 Adverse drug reactions derived from spontaneous reports

Blood and lymphatic system disorders

Thrombocytopenia

Immune System disorders

Anaphylaxis, allergy/hypersensitivity reactions.

Skin and subcutaneous tissue disorders

Urticaria

Hepatobiliary disorders

Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice,

cholestatic jaundice.

Cardiac disorders

Arrhythmias.

Investigations

Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.

Description of selected adverse reactions

Gallbladder and related reactions

Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile

secretion, which may lead to gallbladder abnormalities or sludge. Development of gallstones

has been reported in 15 to 30% of long-term recipients of s.c. Sandostatin. The incidence in

the general population (aged 40 to 60 years) is 5 to 20%. If gallstones do occur, they usually

asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile

acids or by surgery.

Gastrointestinal disorders

In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with

progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

The frequency of gastrointestinal adverse events is known to decrease over time with

continued treatment.

Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time

of Sandostatin s.c. administration, that is, by injecting between meals or on retiring to bed.

Hypersensitivity and anaphylactic reactions

Hypersensitivity and allergic reactions have been reported during post-marketing experience.

When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of

anaphylactic shock have been reported.

Injection site reactions

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness

and swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by

allowing the solution to reach room temperature before injection, or by injecting a smaller

volume using a more concentrated solution.

Metabolism and nutrition disorders

Although measured faecal fat excretion may increase, there is no evidence to date that long-

term treatment with octreotide has led to nutritional deficiency due to malabsorption.

Pancreatic enzymes

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In very rare instances, acute pancreatitis has been reported within the first hours or days of

Sandostatin s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasis

induced pancreatitis has been reported for patients on long-term Sandostatin s.c. treatment.

Cardiac disorders

Bradycardia is a common adverse reaction with somatostatin analogues. In both acromegalic

and carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis

shifts, early repolarisation, low voltage, R/S transition, early R wave progression, and non-

specific ST-T wave changes. The relationship of these events to octreotide acetate is not

established because many of these patients have underlying cardiac diseases (see section 4.4).

Thrombocytopenia

Thrombocytopenia has been reported during post-marketing experience, particularly during

treatment with Sandostatin (i.v.) in patients with cirrhosis of the liver. This is reversible after

discontinuation of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form https://sideeffects.health.gov.il/

4.9

Overdose

A limited number of accidental overdoses of Sandostatin in adults and children have been

reported. In adults, the doses ranged from 2,400-6,000 micrograms/day administered by

continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms three

times a day). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain

hypoxia, pancreatitis, hepatic steatosis, diarrhoea, weakness, lethargy, weight loss,

hepatomegaly, and lactic acidosis.

In children, the doses ranged from 50-3,000 micrograms/day administered by continuous

infusion (2.1-500 micrograms/hour) or subcutaneously (50-100 micrograms). The only

adverse event reported was mild hyperglycaemia.

No unexpected adverse events have been reported in cancer patients receiving Sandostatin at

doses of 3,000-30,000 micrograms/day in divided doses subcutaneously.

The management of overdosage is symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Somatostatin and analogues,

ATC code: H01CB02

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with

similar pharmacological effects, but with a considerably prolonged duration of action. It

inhibits pathologically increased secretion of growth hormone (GH) and of peptides and

serotonin produced within

the GEP endocrine system.

In animals, octreotide is a more potent inhibitor of GH, glucagon and insulin release than

somatostatin is, with greater selectivity for GH and glucagon suppression.

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UK SmPC JAN20

In healthy subjects Sandostatin has been shown to inhibit

release of GH stimulated by arginine, exercise- and insulin-induced hypoglycaemia,

postprandial release of insulin, glucagon, gastrin, other peptides of the GEP endocrine

system, and arginine-stimulated release of insulin and glucagon,

thyrotropin-releasing hormone (TRH)-stimulated release of thyroid-stimulating hormone

(TSH).

Unlike somatostatin, octreotide inhibits GH secretion preferentially over insulin and its

administration is not followed by rebound hypersecretion of hormones (i.e. GH in patients

with acromegaly).

In acromegalic patients Sandostatin lowers plasma levels of GH and IGF-1. A GH reduction

by 50% or more occurs in up to 90% patients, and a reduction of serum GH to <5 ng/mL can

be achieved in about half of the cases. In most patients Sandostatin markedly reduces the

clinical symptoms of the disease, such as headache, skin and soft tissue swelling,

hyperhidrosis, arthralgia, paraesthesia. In patients with a large pituitary adenoma, Sandostatin

treatment may result in some shrinkage of the tumour mass.

In patients with functional tumours of the GEP endocrine system, Sandostatin, because of its

diverse endocrine effects, modifies a number of clinical features. Clinical improvement and

symptomatic benefit occur in patients who still have symptoms related to their tumours

despite previous therapies, which may include surgery, hepatic artery embolization, and

various chemotherapies, e.g. streptozocin and 5-fluorouracil.

Sandostatin's effects in the different tumour types are as follows

Carcinoid tumours

Administration of Sandostatin may result in improvement of symptoms, particularly of

flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and

reduced urinary excretion of 5-hydroxyindole acetic acid.

VIPomas

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal

peptide (VIP). In most cases, administration of Sandostatin results in alleviation of the severe

secretory diarrhoea typical of the condition, with consequent improvement in quality of life.

This is accompanied by an improvement in associated electrolyte abnormalities, e.g.

hypokalaemia, enabling enteral and parenteral fluid and electrolyte supplementation to be

withdrawn. In some patients, computed tomography scanning suggests a slowing or arrest of

progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases.

Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which

may fall into the normal reference range.

Glucagonomas

Administration of Sandostatin results in most cases in substantial improvement of the

necrolytic migratory rash which is characteristic of the condition. The effect of Sandostatin

on the state of mild diabetes mellitus which frequently occurs is not marked and, in general,

does not result in a reduction of requirements for insulin or oral hypoglycaemic agents.

Sandostatin produces improvement of diarrhoea, and hence weight gain, in those patients

affected. Although administration of Sandostatin 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.

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Gastrinomas/Zollinger-Ellison syndrome

Therapy with proton pump inhibitors or H2 receptor blocking agents generally controls

gastric acid hypersecretion. However, diarrhoea, which is also a prominent symptom, may not

be adequately alleviated by proton pump inhibitors or H2 receptor blocking agents.

Sandostatin can help to further reduce gastric acid hypersecretion and improve symptoms,

including diarrhoea, as it provides suppression of elevated gastrin levels, in some patients.

Insulinomas

Administration of Sandostatin produces a fall in circulating immunoreactive insulin, which

may, however, be of short duration (about 2 hours). In patients with operable tumours

Sandostatin may help to restore and maintain normoglycaemia pre-operatively. In patients

with inoperable benign or malignant tumours, glycaemic control may be improved without

concomitant sustained reduction in circulating insulin levels.

GRFomas

These rare tumors are characterized by production of GH releasing factor (GRF) alone or in

conjunction with other active peptides. Sandostatin produces improvement in the features and

symptoms of the resultant acromegaly. This is probably due to inhibition of GRF and GH

secretion, and a reduction in pituitary enlargement may follow

Complications following pancreatic surgery

For patients undergoing pancreatic surgery, the peri- and post-operative administration of

Sandostatin reduces the incidence of typical postoperative complications (e.g. pancreatic

fistula, abscess and subsequent sepsis, postoperative acute pancreatitis).

Bleeding gastro-oesophageal varices

In patients presenting with bleeding gastro-oesophageal varices due to underlying cirrhosis,

Sandostatin administration in combination with specific treatment (e.g. sclerotherapy) is

associated with better control of bleeding and early re-bleeding, reduced transfusion

requirements, and improved 5-day survival. While the precise mode of action of Sandostatin

is not fully elucidated, it is postulated that Sandostatin reduces splanchnic blood flow through

inhibition of vaso-active hormones (e.g. VIP, glucagon).

5.2

Pharmacokinetic properties

Absorption

After s.c. injection, Sandostatin is rapidly and completely absorbed. Peak plasma

concentrations are reached within 30 minutes.

Distribution

The volume of distribution is 0.27 L/kg and the total body clearance 160 mL/min. Plasma

protein binding amounts to 65%. The amount of Sandostatin bound to blood cells is

negligible.

Elimination

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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Sandostatin

0.05mg/ml , solution for injection/ infusion

ןיטטסודנס

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Sandostatin

0.1mg/ml , solution for injection/ infusion

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Sandostatin

0.5mg/ml , solution for injection/ infusion

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ונכדוע

רבמטפס

2020

טמרופ

םינולעה

ןכדוע

םינולעה

וחלשנ

םוסרפל

רגאמב

תופורתה

רתאבש

דרשמ

תואירבה

ןתינו

םלבקל

םיספדומ

לע

ידי

הינפ

לעבל

םושירה

סיטרבונ

לארשי

עב ץראה תרצות ,מ"

.ד.ת ,

7126

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:רישכתה תויוותה

Prevention of complications following pancreatic surgery.

Symptomatic control and reduction of GH and IGF-1plasma levels in patients with acromegaly who

are inadequately controlled by surgery or radiotherapy. Sandostatin treatment is also indicated for

acromegalic patients unfit or unwilling to undergo surgery or in the interim period until radiotherapy

becomes fully effective.

Relief of symptoms associated with functional gastroenteropancreatic endocrine tumours:

- Carcinoid tumours with features of the carcinoid syndrome

- VIPomas

- Glucagonomas

- Gastrinomas / zollinger-Ellison syndrome usually in conjunction with proton pump inhibitors or H2-

antagonist therapy

- Insulinomas for pre-operative control of hypoglycaemia and for maintenance therapy

- GRFomas.

Sandostatin is not an antitumour therapy and is not curative in these patients.

Emergency management of bleeding gastro-oesophageal varices secondary to cirrhosis in

combination with specific therapy such as endoscopic sclerotherapy.

:ליעפ רמוח

לכ לש הלופמא

1

ל"מ

:הליכמ

0.05

/דיטוארטקוא ג"מ

octreotide 0.05 mg

0.1

דיטוארטקוא ג"מ

/

octreotide 0.1 mg

0.5

ג"מ דיטוארטקוא

/

octreotide 0.5 mg

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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:סקפ

9331

03-922

:אפורל ןולע

ןולע

טמרופב

שדח

םינוכדעה

םיווהמה

ןוכדע

עדימב

יתוחיטב

םישגדומ בוהצב

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Sandostatin

0.05mg/ml

Sandostatin

0.1 mg/ ml

Sandostatin

0.5 mg/ml

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

One ampoule of 1 ml contains 0.05, 0.1 or 0.5 mg octreotide (as octreotide acetate)

Excipient(s) with known effect

Contains less than 1 mmol (23 mg) sodium per dose, i.e. is essentially “sodium-free”.

For the full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection /infusion.

Clear, colourless solution.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic Indications

Prevention of complications following pancreatic surgery.

Symptomatic control and reduction of growth hormone (GH) and IGF-1 plasma levels in patients with

acromegaly who are inadequately controlled by surgery or radiotherapy. Sandostatin treatment is also indicated

for acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy

becomes fully effective.

Relief of symptoms associated with functional gastro-entero-pancreatic (GEP) endocrine tumors:

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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Carcinoid tumors with features of the carcinoid syndrome.

VIPomas.

Glucagonomas.

Gastrinomas/Zollinger-Ellison

syndrome,

usually

conjunction

with

proton

pump

inhibitors,

H2-antagonist therapy.

Insulinomas, for pre-operative control of hypoglycemia and for maintenance therapy.

GRFomas.

Sandostatin is not an anti-tumors therapy and is not curative in these patients.

Emergency management of bleeding gastro-esophageal varices secondary to cirrhosis in combination with

specific therapy such as endoscopic sclerotherapy.

4.2.

Posology and method of administration

Posology

General target population

Acromegaly

Initially 0.05 to 0.1 mg by subcutaneous (s.c.) injection every 8 or 12 hours. Dosage adjustment should

be based on monthly assessment of GH and IGF-1 levels (target: GH <2.5 ng/mL; IGF-1 within

normal range) and clinical symptoms, and on tolerability. In most patients, the optimal daily dose will

be 0.3 mg. A maximum dose of 1.5 mg per day should not be exceeded. For patients on a stable dose

of Sandostatin, assessment of GH should be made every 6 months.

If no relevant reduction in GH levels and no improvement in clinical symptoms have been achieved

within 3 months of starting treatment with Sandostatin, therapy should be discontinued.

Gastro-entero-pancreatic endocrine tumours

Initially 0.05 mg once or twice daily by s.c. injection. Depending on clinical response, effect on levels

of tumour-produced hormones (in cases of carcinoid tumours, on the urinary excretion of

5-hydroxyindole acetic acid), and on tolerability, dosage can be gradually increased to 0.1 to 0.2 mg

3 times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses

have to be adjusted individually.

In carcinoid tumours, if there is no beneficial response within 1 week of treatment with Sandostatin at

the maximum tolerated dose, therapy should not be continued.

Complications following pancreatic surgery

0.1 mg 3 times daily by s.c. injection for 7 consecutive days, starting on the day of operation at least

1 hour before laparotomy.

Bleeding gastro-oesophageal varices

25 micrograms/hour for 5 days by continuous intravenous (i.v.) infusion. Sandostatin can be used in

dilution with physiological saline.

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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In cirrhotic patients with bleeding gastro-oesophageal varices, Sandostatin has been well tolerated at

continuous i.v. doses of up to 50 micrograms/hour for 5 days.

Special populations

Geriatric Populations

There is no evidence of reduced tolerability or altered dosage requirements in elderly patients treated

with Sandostatin.

Pediatric Population

Experience with Sandostatin in children is limited.

Hepatic impairment

In patients with liver cirrhosis, the half-life of the drug may be increased, necessitating adjustment of

the maintenance dosage.

Renal impairment

Impaired renal function did not affect the total exposure (AUC) to octreotide administered as s.c.

injection, therefore no dose adjustment of Sandostatin is necessary.

Method of administration

Sandostatin may be administered directly by subcutaneous (s.c.) injection or by intravenous (i.v.)

infusion after dilution. For further instructions on handling and instructions for dilution of the

medicinal product, refer to section 6.6.

4.3.

Contraindications

Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4

Special warnings and precautions for use

General

As GH-secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual

field defects), it is essential that all patients be carefully monitored. If evidence of tumour expansion

appears, alternative procedures may be advisable.

The therapeutic benefits of a reduction in growth hormone (GH) levels and normalisation of insulin-

like growth factor 1 (IGF-1) concentration in female acromegalic patients could potentially restore

fertility. Female patients of childbearing potential should be advised to use adequate contraception if

necessary during treatment with octreotide (see section 4.6).

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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Thyroid function should be monitored in patients receiving prolonged treatment with octreotide.

Hepatic function should be monitored during octreotide therapy.

Cardiovascular related events

Common cases of bradycardia have been reported. Dose adjustments of medicinal products such as

beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be

necessary (see section 4.5).

Gallbladder and related events

Cholelithiasis is a very common event during Sandostatin treatment and may be associated with

cholecystitis and biliary duct dilatation (see section 4.8).

Ultrasonic examination of the gallbladder

before, and at about 6- to 12-month intervals during Sandostatin therapy is therefore recommended.

GEP endocrine tumours

During the treatment of GEP endocrine tumours, there may be rare instances of sudden escape from

symptomatic control by Sandostatin, with rapid recurrence of severe symptoms. If the treatment is

stopped, symptoms may worsen or recur.

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon, and insulin, Sandostatin may affect

glucose regulation. Post-prandial glucose tolerance may be impaired and, in some instances, the state

of persistent hyperglycaemia may be induced as a result of chronic administration. Hypoglycaemia has

also been reported.

In patients with insulinomas, octreotide, because of its greater relative potency in inhibiting the

secretion of GH and glucagon than that of insulin, and because of the shorter duration of its inhibitory

action on insulin, may increase the depth and prolong the duration of hypoglycaemia. These patients

should be closely monitored during initiation of Sandostatin therapy and at each change of dosage.

Marked fluctuations in blood glucose concentration may possibly be reduced by smaller, more

frequently administered doses.

Insulin requirements of patients with type I diabetes mellitus therapy may be reduced by

administration of Sandostatin. In non-diabetics and type II diabetics with partially intact insulin

reserves, Sandostatin administration can result in post-prandial increases in glycaemia. It is therefore

recommended to monitor glucose tolerance and antidiabetic treatment.

Oesophageal varices

Since, following bleeding episodes from oesophageal varices, there is an increased risk for the

development of insulin-dependent diabetes or for changes in insulin requirement in patients with

pre-existing diabetes, an appropriate monitoring of blood glucose levels is mandatory.

Local Site Reactions

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

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In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the s.c. injection

site only at the highest dose (about 8 times the maximum human dose based on body surface area). No

hyperplastic or neoplastic lesions occurred at the s.c. injection site in a 52-week dog toxicity study.

There have been no reports of tumour formation at the injection sites in patients treated with

Sandostatin for up to 15 years. All the information available at present indicates that the findings in

rats are species specific and have no significance for the use of the drug in humans (see section 5.3).

Nutrition

Octreotide may alter absorption of dietary fats in some patients.

Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients

receiving octreotide therapy. Monitoring of vitamin B12 levels is recommended during therapy with

Sandostatin in patients who have a history of vitamin B12 deprivation.

Sodium content

Sandostatin contains less than 1 mmol (23 mg) sodium per dose, i.e is essentially “sodium-

free”.

4.5

Interactions with other medicinal products and other forms of interaction

Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to

control fluid and electrolyte balance may be necessary when Sandostatin is administered

concomitantly (see section 4.4).

Dose adjustments of insulin and antidiabetic medicinal products may be required when Sandostatin is

administered concomitantly (see section 4.4).

Sandostatin has been found to reduce the intestinal absorption of cyclosporin and to delay that of

cimetidine.

Concomitant administration of octreotide and bromocriptine increases the bioavailability of

bromocriptine.

Limited published data indicate that somatostatin analogues might decrease the metabolic clearance of

compounds known to be metabolised by cytochrome P450 enzymes, which may be due to the

suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other

drugs mainly metabolised by CYP3A4 and which have a low therapeutic index should therefore be

used with caution (e.g. quinidine, terfenadine).

4.6.

Fertility, pregnancy and lactation

Pregnancy

There is a limited amount of data (less than 300 pregnancy outcomes) from the use of octreotide in

pregnant women, and in approximately one third of the cases the pregnancy outcomes are unknown.

The majority of reports were received after post-marketing use of octreotide and more than 50% of

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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exposed pregnancies were reported in patients with acromegaly. Most women were exposed to

octreotide during the first trimester of pregnancy at doses ranging from 100-1200 micrograms/day of

Sandostatin s.c. or 10-40 mg/month of Sandostatin LAR. Congenital anomalies were reported in about

4% of pregnancy cases for which the outcome is known. No causal relationship to octreotide is

suspected for these cases.

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 the use of Sandostatin during pregnancy (see

section 4.4).

Breastfeeding

It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown

excretion of octreotide in breast milk. Patients should not breast-feed during Sandostatin treatment.

Fertility

It is not known whether octreotide has an effect on human fertility. Late descent of the testes was

found for male offsprings of dam treated during pregnancy and lactation. Octreotide, however, did not

impair fertility in male and female rats at doses of up to 1 mg/kg body weight per day (see

section 5.3).

4.7.

Effects on ability to drive and use machines

Sandostatin has no or negligible influence on the ability to drive and use machines. Patients should be

advised to be cautious when driving or using machines if they experience dizziness, asthenia/fatigue,

or headache during treatment with Sandostatin.

4.8

Undesirable effects

Summary of the safety profile

The most frequent adverse reactions reported during octreotide therapy include gastrointestinal

disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.

The most commonly reported adverse reactions in clinical trials with octreotide administration were

diarrhoea, abdominal pain, nausea, flatulence, headache, cholelithiasis, hyperglycaemia and

constipation. Other commonly reported adverse reactions were dizziness, localised pain, biliary

sludge, thyroid dysfunction (e.g. decreased thyroid stimulating hormone [TSH], decreased total T4,

and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and

hypoglycaemia.

Tabulated list of adverse reactions

The following adverse drug reactions, listed in Table 1, have been accumulated from clinical studies

with octreotide:

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Adverse drug reactions (Table 1) are ranked under heading of frequency, the most frequent first, using

the following convention: very common (

1/10); common (

1/100, < 1/10); uncommon (

1/1,000, ≤

1/100); rare (

1/10,000, ≤ 1/1,000) very rare (≤ 1/10,000), including isolated reports. Within each

frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Table 1 Adverse drug reactions reported in clinical studies

Gastrointestinal disorders

Very common:

Diarrhoea, abdominal pain, nausea, constipation, flatulence.

Common:

Dyspepsia, vomiting, abdominal bloating, steatorrhoea, loose

stools, discolouration of faeces.

Nervous system disorders

Very common:

Headache.

Common:

Dizziness.

Endocrine disorders

Common:

Hypothyroidism, thyroid disorder (e.g. decreased TSH,

decreased total T4, and decreased free T4).

Hepatobiliary disorders

Very common:

Cholelithiasis.

Common:

Cholecystitis, biliary sludge, hyperbilirubinaemia.

Metabolism and nutrition disorders

Very common:

Hyperglycaemia.

Common:

Hypoglycaemia, impaired glucose tolerance, anorexia.

Uncommon:

Dehydration.

General disorders and administration site conditions

Very common:

Injection site reactions.

Common:

Asthenia.

Investigations

Common:

Elevated transaminase levels.

Skin and subcutaneous tissue disorders

Common:

Pruritus, rash, alopecia.

Respiratory disorders

Common:

Dyspnoea.

Cardiac disorders

Common:

Bradycardia

Uncommon:

Tachycardia.

Post-marketing

Spontaneously reported

adverse reactions presented in Table 2, are reported voluntarily and it is not

always possible to reliably establish frequency or a causal relationship to drug exposure

.

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Table 2 Adverse drug reactions derived from spontaneous reports

Blood and lymphatic system disorders

Thrombocytopenia

Immune System disorders

Anaphylaxis, allergy/hypersensitivity reactions.

Skin and subcutaneous tissue disorders

Urticaria

Hepatobiliary disorders

Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice,

cholestatic jaundice.

Cardiac disorders

Arrhythmias.

Investigations

Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.

Description of selected adverse reactions

Gallbladder and related reactions

Somatostatin analogues have been shown to inhibit gallbladder contractility and decrease bile

secretion, which may lead to gallbladder abnormalities or sludge. Development of gallstones has been

reported in 15 to 30% of long-term recipients of s.c. Sandostatin. The incidence in the general

population (aged 40 to 60 years) is 5 to 20%. If gallstones do occur, they usually asymptomatic;

symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

Gastrointestinal disorders

In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with

progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

The frequency of gastrointestinal adverse events is known to decrease over time with continued

treatment.

Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of

Sandostatin s.c. administration, that is, by injecting between meals or on retiring to bed.

Hypersensitivity and anaphylactic reactions

Hypersensitivity and allergic reactions have been reported during post-marketing experience. When

these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic

shock have been reported.

Injection site reactions

Pain or a sensation of stinging, tingling or burning at the site of s.c. injection, with redness and

swelling, rarely lasting more than 15 minutes. Local discomfort may be reduced by allowing the

solution to reach room temperature before injection, or by injecting a smaller volume using a more

concentrated solution.

Metabolism and nutrition disorders

Although measured faecal fat excretion may increase, there is no evidence to date that long- term

treatment with octreotide has led to nutritional deficiency due to malabsorption.

Novartis Israel Ltd.

6 Tozeret Haaretz street, Tel Aviv

P.O.Box 7126

Tel: 972-3-9201111 Fax: 972-3-9229331

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Pancreatic enzymes

In very rare instances, acute pancreatitis has been reported within the first hours or days of Sandostatin

s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasis induced pancreatitis

has been reported for patients on long-term Sandostatin s.c. treatment.

Cardiac disorders

Bradycardia is a common adverse reaction with somatostatin analogues. In both acromegalic and

carcinoid syndrome patients, ECG changes were observed such as QT prolongation, axis shifts, early

repolarisation, low voltage, R/S transition, early R wave progression, and non-specific ST-T wave

changes. The relationship of these events to octreotide acetate is not established because many of

these patients have underlying cardiac diseases (see section 4.4).

Thrombocytopenia

Thrombocytopenia has been reported during post-marketing experience, particularly during treatment

with Sandostatin (i.v.) in patients with cirrhosis of the liver. This is reversible after discontinuation of

treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form https://sideeffects.health.gov.il/

4.9

Overdose

A limited number of accidental overdoses of Sandostatin in adults and children have been reported. In

adults, the doses ranged from 2,400-6,000 micrograms/day administered by continuous infusion (100-

250 micrograms/hour) or subcutaneously (1,500 micrograms three times a day). The adverse events

reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatic steatosis,

diarrhoea, weakness, lethargy, weight loss, hepatomegaly, and lactic acidosis.

In children, the doses ranged from 50-3,000 micrograms/day administered by continuous infusion

(2.1-500 micrograms/hour) or subcutaneously (50-100 micrograms). The only adverse event reported

was mild hyperglycaemia.

No unexpected adverse events have been reported in cancer patients receiving Sandostatin at doses of

3,000-30,000 micrograms/day in divided doses subcutaneously.

The management of overdosage is symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Somatostatin and analogues,

ATC code: H01CB02

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