4.1. Therapeutic indications

Treatment of patients with acromegaly in whom surgery is inappropriate or ineffective, or in the interim period until radiotherapy becomes fully effective (see section 4.2).

Treatment of patients with symptoms associated with functional gastro-entero-pancreatic endocrine tumours e.g. carcinoid tumours with features of the carcinoid syndrome (see section 5.1).

Treatment of patients with advanced neuroendocrine tumours of the midgut or of unknown primary origin where non-midgut sites of origin have been excluded.

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

It is recommended to start treatment with the administration of 20 mg Olatuton at 4-week intervals for 3 months. Patients on treatment with s.c. octreotide can start treatment with Olatuton the day after the last dose of s.c. octreotide. Subsequent dosage adjustment should be based on serum growth hormone (GH) and insulin-like growth factor 1/somatomedin C (IGF-1) concentrations and clinical symptoms.

For patients in whom, within this 3-month period, clinical symptoms and biochemical parameters (GH; IGF-1) are not fully controlled (GH concentrations still above 2.5 microgram/L), the dose may be increased to 30 mg every 4 weeks. If after 3 months, GH, IGF-1, and/or symptoms are not adequately controlled at a dose of 30 mg, the dose may be increased to 40 mg every 4 weeks.

For patients whose GH concentrations are consistently below 1 microgram/L, whose IGF-1 serum concentrations normalised, and in whom most reversible signs/symptoms of acromegaly have disappeared after 3 months of treatment with 20 mg, 10 mg Olatuton may be administered every 4 weeks. However, particularly in this group of patients, it is recommended to closely monitor adequate control of serum GH and IGF-1 concentrations, and clinical signs/symptoms at this low dose of Olatuton.

For patients on a stable dose of Olatuton, assessment of GH and IGF-1 should be made every 6 months.

Gastro-entero-pancreatic endocrine tumours

Treatment of patients with symptoms associated with functional gastro-entero-pancreatic neuroendocrine tumours

It is recommended to start treatment with the administration of 20 mg Olatuton at 4-week intervals. Patients on treatment with s.c. octreotide should continue at the previously effective dosage for 2 weeks after the first injection of Olatuton.

For patients in whom symptoms and biological markers are well controlled after 3 months of treatment, the dose may be reduced to 10 mg Olatuton every 4 weeks.

For patients in whom symptoms are only partially controlled after 3 months of treatment, the dose may be increased to 30 mg Olatuton every 4 weeks.

For days when symptoms associated with gastro-entero-pancreatic tumours may increase during treatment with Olatuton, additional administration of s.c. octreotide is recommended at the dose used prior to the Olatuton treatment. This may occur mainly in the first 2 months of treatment until therapeutic concentrations of octreotide are reached.

Treatment of patients with advanced neuroendocrine tumours of the midgut or of unknown primary origin where non-midgut sites of origin have been excluded

The recommended dose of Olatuton is 30 mg administered every 4 weeks (see section 5.1). Treatment with Olatuton for tumour control should be continued in the absence of tumour progression.

Treatment of TSH-secreting adenomas

Treatment with Olatuton should be started at a dose of 20 mg at 4-weekly intervals for 3 months before considering dose adjustment. The dose is then adjusted on the basis of the TSH and thyroid hormone response.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC) to octreotide when administered s.c. Therefore, no dose adjustment of Olatuton is necessary.

Use in patients with impaired hepatic function

In a study with octreotide administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In certain cases patients with impaired hepatic function may require dose adjustment.

Use in the elderly

In a study with octreotide administered s.c., no dose adjustment was necessary in subjects ≥ 65 years of age. Therefore, no dose adjustment is necessary in this group of patients with Olatuton.

Use in children

There is limited experience with the use of Olatuton in children.

Method of administration

Olatuton may only be administered by deep intramuscular injection. The site of repeat intramuscular injections should be alternated between the left and right gluteal muscle (see section 6.6).

4.3. Contraindications

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 adjustment 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 octreotide 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 octreotide prolonged-release injection in the post-marketing setting.

Ultrasonic examination of the gallbladder before and at about 6-monthly intervals during octreotide prolonged-release injection therapy is recommended.

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon, and insulin release, Olatuton may affect glucose regulation. Post-prandial glucose tolerance may be impaired. As reported for patients treated with s.c. octreotide, 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 concomitant Type I diabetes mellitus, Olatuton is likely to affect glucose regulation, and insulin requirements may be reduced. In non-diabetics and type II diabetics with partially intact insulin reserves, octretoide s.c. administration may result in increases in post-prandial glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.

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.

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.

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

Sodium content

Olatuton contains less than 1 mmol (23 mg) sodium per dose, 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 Olatuton is administered concomitantly (see section 4.4).

Dose adjustments of insulin and antidiabetic medicinal products may be required when Olatuton is administered concomitantly (see section 4.4).

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

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 Olatuton should be avoided for at least 4 weeks prior to the administration of lutetium (177 Lu) oxodotreotide, a radiopharmaceutical binding to somatostatin receptors. If necessary, patients may be treated with short acting somatostatin analogues until 24 hours prior to the administration of lutetium (177Lu) oxodotreotide.

After administration of lutetium (177Lu) oxodotreotide, treatment with Olatuton can be resumed within 4 to 24 hours and should be discontinued again 4 weeks prior to the next administration of lutetium (177Lu) oxodotreotide.

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 octreotide s.c. or 10-40 mg/month of octreotide long-acting injection. 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 Olatuton during pregnancy (see section 4.4).

Breast-feeding

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 Olatuton 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 dams 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

Olatuton 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 Olatuton.

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, thoracic and mediastinal 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. octreotide. The incidence in the general population (aged 40 to 60 years) is about 5 to 20%. Long-term exposure to octreotide prolonged-release injection of patients with acromegaly or gastro-entero-pancreatic tumours suggests that treatment with octreotide prolonged-release injection does not increase the incidence of gallstone formation, compared with s.c. treatment. If gallstones do occur, they are 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.

Hypersensitivity and anaphylactic reactions

Hypersensitivity and allergic reactions have been reported during post-marketing. When these occur, they mostly affect the skin, rarely the mouth and airways. Isolated cases of anaphylactic shock have been reported.

Injection site reactions

Injection site related reactions including pain, redness, haemorrhage, pruritus, swelling or induration were commonly reported in patients receiving octreotide prolonged-release injection; however, these events did not require any clinical intervention in the majority of the cases.

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 octreotide s.c. treatment and resolved on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide 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 octreotide injection (i.v.) in patients with cirrhosis of the liver, and during treatment with octreotide prolonged-release injection. 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

A limited number of accidental overdoses of octreotide prolonged-release injection have been reported. The doses ranged from 100 mg to 163 mg/month of octreotide prolonged-release injection. The only adverse event reported was hot flushes.

Cancer patients receiving doses of octreotide prolonged-release injection up to 60 mg/month and up to 90 mg/2 weeks have been reported. These doses were in general well tolerated; however, the following adverse events have been reported: frequent urination, fatigue, depression, anxiety, and lack of concentration.

The management of overdosage is symptomatic.