4.1. Therapeutic indications

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 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 tumours, e.g. carcinoid tumours with features of the carcinoid syndrome (see section 5.1).

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

Prevention of complications following pancreatic surgery.

Emergency management to stop bleeding and to protect from re-bleeding owing to gastro-oesophageal varices in patients with cirrhosis. Sandostatin is to be used in association with specific treatment such as endoscopic sclerotherapy.

Treatment of TSH-secreting pituitary adenomas:

• when secretion has not normalised after surgery and/or radiotherapy;

• in patients in whom surgery is inappropriate;

• in irradiated patients, until radiotherapy is effective.

4.2. Posology and method of administration

Posology

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 and IGF-1 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 surgery 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 (see Section 4.9).

Treatment of TSH-secreting pituitary adenomas

The dosage most generally effective is 100 micrograms three times a day by s.c. injection. The dose can be adjusted according to the responses of TSH and thyroid hormones. At least 5 days of treatment will be needed to judge the efficacy.

Use in the elderly

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

Use in children

Experience with Sandostatin in children is limited.

Use in patients with impaired liver function

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

Use in patients with impaired renal function

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).

Atrioventricular blocks (including complete atrioventricular block) were reported in patients receiving high doses of continuous infusion (100 micrograms/hour) and in patients receiving bolus octreotide intravenously (50 micrograms bolus followed by 50 micrograms/hour continuous infusion). The maximum dose of 50 microgram/hour should therefore not be exceeded (see section 4.2). Patients who receive high doses of intravenous octreotide should be kept under appropriate cardiac monitoring.

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). Additionally, cases of cholangitis have been reported as a complication of cholelithiasis in patients taking Sandostatin in the post-marketing setting. 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

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.

Pancreatic function

Pancreatic exocrine insufficiency (PEI) has been observed in some patients receiving octreotide therapy for gastroenteropancreatic neuroendocrine tumours. Symptoms of PEI can include steatorrhea, loose stools, abdominal bloating and weight loss. Screening and appropriate treatment for PEI according to clinical guidelines should be considered in symptomatic patients.

Sodium content

Sandostatin contains less than 1 mmol (23 mg) sodium per ampoule/vial, that is to say essentially 'sodium-free'.

4.5. Interaction 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 ciclosporin 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).

Concomitant use with radioactive somatostatin analogues

Somatostatin and its analogues such as octreotide competitively bind to somatostatin receptors and may interfere with the efficacy of radioactive somatostatin analogues.

The administration of Sandostatin should be avoided for 24 hours prior to the administration of lutetium (177Lu) oxodotreotide, a radiopharmaceutical binding to somatostatin receptors.

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

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

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

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 (1,000 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. Atrioventricular blocks (including complete atrioventricular block) were reported in patients receiving 100 micrograms/hour of continuous infusion and/or bolus octreotide intravenously (50 micrograms bolus followed by 50 micrograms/hour continuous infusion).

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.