Octreotide 100 micrograms/ml solution for injection

One ampoule of 1 ml solution for injection contains octreotide acetate equivalent to 0.1 milligrams of octreotide.

For full list of excipients, see Section 6.1.

Solution for injection.

A clear colourless solution.

GEP tumours

For the relief of symptoms associated with functional gastroenteropancreatic endocrine tumours including:

- carcinoid tumours with features of carcinoid syndrome

- VIPomas

- glucagonomas

Octreotide is not antitumour therapy and is not curative in these patients.

Acromegaly

For symptomatic control and reduction of growth hormone (GH) and Insulin-like growth factor number-1 (IGF-1) levels in patients with acromegaly who are not adequately controlled by surgery or radiotherapy:

- in short term treatment, prior to pituitary surgery, or

- in long term treatment in those who are inadequately controlled by pituitary surgery, radiotherapy, dopamine agonist treatment, or in the interim period until radiotherapy becomes effective.

Octreotide is indicated for acromegalic patients for whom surgery is inappropriate.

Prevention of complications following pancreatic surgery

Route of administration

Subcutaneous or intravenous use.

GEP tumours

Initially a dose of 0.05 mg once or twice daily by s.c. injection. Depending on response, dosage can be gradually increased to 0.2 mg three times daily. Under exceptional circumstances, higher doses may be required. Maintenance doses are variable.

The recommended route of administration is subcutaneous, however, in instances where a rapid response is required, e.g. carcinoid crises, the initial recommended dose of octreotide may be administered by the intravenous route, diluted and given as a bolus, whilst monitoring the cardiac rhythm.

In carcinoid tumours, if there is no beneficial effect within a week, continued therapy is not recommended.

Acromegaly

Initially 0.05 - 0.1 mg subcutaneously every 8 or 12 hours. For most patients the optimal daily dose is normally 0.2 – 0.3 mg daily. More than 1.5 mg per day should not be given. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH less than 2.5ng/ml, 5mU/l; IGF-1 within normal range) and clinical symptoms, and on tolerability. For patients on a stable dose of octreotide, assessment of GH should be made every 6 months.

If no relevant reduction of growth hormone levels and no improvement of clinical symptoms have been achieved within three months of starting treatment, therapy should be discontinued.

For the prevention of complications following pancreatic surgery

0.1 mg three times daily by subcutaneous injection for 7 consecutive days, starting on the day of operation at least one hour before laparotomy.

Use in patients with impaired renal function

Impaired renal function did not affect the total exposure (AUC; area under the curve) to octreotide when administered s.c. therefore, no dose adjustment of octreotide is necessary.

Use in patients with impaired hepatic function

In patients with liver cirrhosis the half-life of Octreotide may be increased, requiring an adjustment of the maintenance dose.

Elderly

In elderly patients treated with octreotide, there is no evidence for reduced tolerability or altered dosage requirements.

Paediatric population

Experience with octreotide in children is very limited.

Ampoules: for instructions on i.v. administration, see section 6.6.

Known hypersensitivity to octreotide or to any component of the formulations (see 6.1 List of excipients).

Octreotide solution for injection contains less than 1mmol (23mg) sodium per ml solution, i.e. essentially 'sodium-free'.

General

77As growth hormone 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 child bearing potential should be advised to use adequate contraception if necessary during treatment with octreotide (see also section 4.6 Pregnancy and lactation).

Thyroid function should be monitored in patients receiving long-term octreotide therapy.

Cardiovascular related events

Uncommon cases of bradycardia have been reported. Dose adjustments of drugs such as beta-blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may be necessary.

GEP endocrine tumours

Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by octreotide may occur infrequently, with rapid recurrence of severe symptoms.

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon, and insulin release, octreotide may affect glucose regulation. Postprandial 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 observed.

Octreotide may increase the depth and duration of hypoglycaemia in patients with insulinoma. This is because it is relatively more potent in inhibiting growth hormone and glucagon secretion than in inhibiting insulin and because its duration of insulin inhibition is shorter. If octreotide is given to a patient with insulinoma, close monitoring is necessary on introduction of therapy and at each change of dosage. Marked fluctuations of blood glucose may be reduced by more frequent administration of octreotide.

Octreotide may reduce insulin or oral hypoglycaemic requirements in patients with type I diabetes mellitus. In non-diabetics and type II diabetics with particularly intact insulin reserves, octreotide administration can result in prandial increases in glycaemia. It is therefore recommended to monitor glucose tolerance and antidiabetic treatment.

Gallbladder and related events

Octreotide exerts an inhibiting effect on gallbladder motility, bile acid secretion and bile flow and there is an acknowledged association with the development of gallstones. The incidence of gallstone formation with octreotide treatment is estimated to be between 15 - 30 %.

Ultrasonic examination of the gallbladder, before and at about 6 to 12 month intervals during octreotide therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated in the normal manner with due attention to abrupt withdrawal of the drug.

In patients with cirrhosis, dosage adjustment may be necessary (see Section 4.2 Posology and Method of Administration).

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 40 times the maximum human dose). 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 Octreotide 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.

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

Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine.

Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine.

Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized 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. quinine, carbamazepine, digoxin, warfarin and terfenadine).

Octreotide reduces the hepatic blood flow with about 30%. The risk of interactions with constituents for which the metabolism is dependent on liver blood flow needs therefore to be taken into account.

Pregnancy

Pregnant women should be given the drug only in compelling circumstances.

Insufficient data exist on the use of Octreotide in pregnant women. Due to its growth hormone inhibiting effect, it may be assumed that Octreotide poses a risk to the foetus.

Studies in animals showed transient growth retardation of offspring before weaning (see section 5.3), possibly consequent upon the specific endocrine profiles of species tested, but there was no evidence of foetotoxic, teratogenic or other reproductive effects.

The potential risk for humans is unknown.

Lactation

Women receiving treatment with octreotide should not breastfeed their infants. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk.

No data exists on the effects of octreotide on the ability to drive and use machines.

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.

In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding.

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.

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.

Occurrence of gastrointestinal side-effects may be reduced by avoiding meals around the time of octreotide administration, that is, by injecting between meals or on retiring to bed.

In rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hours or days of Octreotide treatment and resolves on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term Octreotide treatment.

There have been isolated cases of biliary colic following the abrupt withdrawal of the drug in acromegalic patients in whom biliary sludge or gallstones had developed.

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 Special warnings and precautions for use).

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

A limited number of accidental overdoses of Octreotide in adults and children have been reported. In adults, the doses ranged from 2400-6000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1500 micrograms t.i.d.). The adverse events reported were arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, diarrhoea, weakness, lethargy, weight loss, hepatomegaly and lactic acidosis.

In children, the doses ranged from 50-3000 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 Octreotide at doses of 3000-30,000 micrograms/day in divided doses subcutaneously.

The management of overdosage is symptomatic.

Pharmacotherapeutic group: Antigrowth hormones (ATC code H01CB02).

Octreotide is a synthetic octapeptide derivative of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone and of peptides and serotonin produced within the gastroenteropancreatic endocrine (GEP) system.

In animals, octreotide is a more potent inhibitor of growth hormone, glucagon and insulin release than somatostatin with greater selectivity for growth hormone and glucagon suppression.

In normal healthy subjects octreotide, like somatostatin, has been shown to inhibit

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

- postprandial release of insulin, glucagon, gastrin other peptides of the gastroenteropancreatic system; arginine-stimulated release of insulin and glucagon and

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

Unlike somatostatin, octreotide inhibits growth hormone preferentially over insulin and its administration is not followed by rebound hypersecretion of hormones (i.e. growth hormone in patients with acromegaly).

For patients undergoing pancreatic surgery, the peri and post-operative administration of octreotide reduces the incidence of typical post-operative complications (e.g. pancreatic fistula, abscess and subsequent sepsis, post-operative acute pancreatitis).

In patients with acromegaly, octreotide consistently lowers GH and normalises IGF-1 serum concentrations in the majority of patients. In most patients, octreotide markedly reduces the clinical symptoms of the disease, such as headache, perspiration, paresthesia, fatigue, osteoarthralgia and carpal tunnel syndrome. In individual patients with GH-secreting pituitary adenoma, octreotide was reported to lead to shrinkage of the tumour mass.

For patients with functional tumours of the gastroenteropancreatic endocrine system, treatment with octreotide provides continuous control of symptoms related to the underlying disease. The effects of octreotide in different types of gastroenteropancreatic tumours are as follows:

The effect of Octreotide on tumour size, rate of growth or on the formation of metastases has not yet been clearly documented.

Carcinoid tumours

Administration of octreotide may result in improvement of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a falling 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 octreotide 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. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

Glucagonomas

Administration of octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of the condition. The effect of octreotide 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. Octreotide produces improvement of diarrhoea, and hence weight gain, in those patients affected. Although administration of octreotide often leads to an immediate reduction in plasma glucagon levels, this decrease is generally not maintained over a prolonged period of administration, despite continued symptomatic improvement.

Prevention of complications after pancreatic surgery

Studies showed that especially the incidence of development of fistula decreases with perioperative or postoperative administration of octreotide in pancreatic surgery. The incidence of other specific, postoperative complications, such as development of abscess with the risk of emerging sepsis and acute pancreatitis, are influenced to a lesser extent. Patients were examined who had to undergo elective pancreas resection and/or pancreaticojejunostomy on account of a pancreas tumour, periampullar carcinoma or chronic pancreatitis.

Absorption

After subcutaneous injection, octreotide 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 octreotide bound to blood cells is negligible.

Elimination

The elimination half-life after subcutaneous administrations is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and 90 minutes respectively. About 32 % is excreted unchanged into the urine.

Renal insufficiency did not affect the total exposure (AUC) to Octreotide when administered in the form of a subcutaneous injection. The elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver.

Preclinical data reveal no specific hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Studies in animals showed transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles of the species tested, but there was no evidence of foetotoxic, teratogenic, or other reproduction effects.

Sodium acetate trihydrate

Glacial acetic acid

Sodium chloride

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Ampoules: Shelf-life as packed for sale: 2 years.

Unopened ampoules may be stored at 25 °C for up to two weeks.

Chemical and physical in-use stability of the diluted solution has been demonstrated for 8 hours at 25°C. From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Ampoules:

Store in a refrigerator (2 - 8 °C). Do not freeze. Keep the ampoules in the outer carton in order to protect from light.

For storage of the diluted product reference is given to section 6.6.

Ampoules: 1 ml solution in an ampoule of uncoloured glass.

Boxes of 5, 10 or 30 ampoules.

Not all pack sizes may be marketed.

Ampoules:

Ampoules should be opened immediately prior to use and any unused solution should be discarded.

To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.

Administration by the subcutaneous route:

Octreotide should be administered by the subcutaneous route without dilution.

Administration by the intravenous route:

For i.v. use octreotide should be diluted with normal saline to a ratio of not less than 1 vol : 1 vol and not more than 1 vol : 9 vol . Dilution of octreotide with glucose solution is not recommended.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Sun Pharmaceuticals UK Limited

1200 Century Way,

Thorpe Business Park,

Colton

Leeds

LS15 8 ZA

UK

PL 24897/0002

12^th May 2008

18/04/2012