OLATUTON Powder and solvent for suspension for injection Ref.[49976] Active ingredients: Octreotide

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’.

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.

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).

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.

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:

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:

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 prolonged-release injection (i.v.) in patients with cirrhosis of the liver, and during treatment with octreotide 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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.