SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Octreotide 50 micrograms/ml Solution for Injection or Concentrate for Solution for Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of Octreotide solution for injection or concentrate for solution for infusion contains 50 micrograms of octreotide (as octreotide acetate).

Octreotide solution for injection or concentrate for solution for infusion contains less than 1 mmol (23 mg) sodium per dose, i.e essentially “sodium-free”.

For a full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection (s.c) or concentrate for solution for infusion.

pH:    3.7 to 4.7

Osmolality:    315 to 350 mOsmol/kg

The solution is clear and colourless.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

GEP tumours:

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

Carcinoid tumours with features of carcinoid syndrome

VIPomas

Glucagonomas

Acromegaly:

For symptomatic control and reduction of growth hormone and somatomedin c plasma levels in patients with acromegaly:

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

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

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

Evidence from short term studies demonstrate that tumour size is reduced in some patients (prior to surgery) further tumour shrinkage however cannot be expected as a feature of continued long term treatment.

Prevention of complications following pancreatic surgery.

4.2 Posology and method of administration

Route of administration

Subcutaneous or intravenous use.

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

GEP tumours

Initially 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.

0.1 - 0.2 mg three times daily by s.c. injection. Dosage adjustment should be based on monthly assessment of GH and IGF-1 levels (target: GH less than 2.5 ng/ml, 5mU/I; 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 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is adequate.

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 subcutaneously, and therefore no dose adjustment of Octreotide is necessary.

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 the elderly:

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

Paediatric population:

Experience with the use of Octreotide in children is very limited.

4.3 Contraindications

Known hypersensitivity to octreotide or to any of the excipients.

4.4 Special warnings and precautions for use General

As 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).

Thyroid function (TSH and thyroid hormone levels) 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). 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.

4.5 Interaction with other medicinal products and other forms of interaction

Octreotide has been reported to reduce the intestinal absorption of ciclosporin 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. carbamazepine, digoxin, terfenadine).

4.6 Fertility, pregnancy and lactation

Pregnancy

Octreotide should only be prescribed to pregnant women under compelling circumstances (see also section 4.4).

There are no adequate and well-controlled studies in pregnant women. In the postmarketing experience, data on a limited number of exposed pregnancies have been reported in patients with acromegaly, however, in half of the cases the pregnancy outcomes are unknown. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 micrograms/day of Octreotide s.c. or 20-30 mg/month of Octreotide LAR. In approximately two-thirds of the cases with known outcome, the women elected to continue octreotide therapy during their pregnancies. In most of the cases with known outcome, normal newborns were reported, but also several spontaneous abortions during the first trimester, and a few induced abortions.

There were no cases of congenital anomalies or malformations due to octreotide usage in the cases that reported pregnancy outcomes.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development apart from some transient retardation of physiological growth (see section 5.3).

Lactation

Patients should not breastfeed during Octreotide treatment. It is unknown whether octreotide is excreted in human breast milk. Animal studies have shown excretion of octreotide in breast milk.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

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).

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 to <1/10); uncommon (^1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); Not known (cannot be estimated from the available data) including isolated reports. Within each frequency grouping adverse reactions are ranked in order of decreasing seriousness.

Table - Adverse drug reactions

Endocrine disorders
Common:	Hypothyroidism, thyroid dysfunction (e.g., decreased TSH, decreased Total T4 and decreased Free T4)
Metabolism and nutrition disorders:
Very common:	Hyperglycaemia
Common:	Hypoglycaemia, impaired glucose tolerance, anorexia
Uncommon:	Dehydration
Cardiac disorders
Common:	Bradycardia

Uncommon:	Tachycardia
Not Known:	Arrhythmias
Respiratory disorders
Common:	Dyspnoea
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
Hepatobillary disorders
Very common:	Cholelithiasis
Common:	Cholecystitis, biliary sludge, hyperbilirubinaemia
Not known	Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis, cholestasis, jaundice, cholestatic jaundice
Skin and subcutaneous tissue disorder
Common:	Pruritus, rash, alopecia
Not known	Urticaria
General disorders and administration site
Very common:	Injection site localised pain
Investigations
Common:	Elevated transaminase levels
Not known	Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels
Immune disorders
Not known	Anaphylaxis, allergy/hypersensitivity reactions

4.9 Overdose

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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 effect of octreotide in different types of gastroenteropancreatic tumours are as follows:

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 characteristics 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.

5.2 Pharmacokinetic properties Absorption

After subcutaneous administration, Octreotide is rapidly and completely absorbed. The peak plasma concentration is 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 is approximately 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. About 32% is excreted unchanged in the urine.

5.3 Preclinical safety data

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.

6.1    List of excipients

Glacial acetic acid (for pH adjustment)

Sodium acetate trihydrate (for pH adjustment) (E262)

Mannitol (E421)

Water for injections

6.2    Incompatibilities

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

6.3 Shelf life

Unopened vials: 3 years

Shelf life after first opening: The product must be used immediately and any unused drug product must be discarded.

Storage conditions after dilution: The chemical and physical stability of Octreotide solution diluted in 9 mg/ml (0.9%) sodium chloride solution for infusion has been demonstrated for 24 hours when stored below 25°C. From a microbiological point of view, the product should be used immediately, if not used immediately, storage times and conditions are the responsibility of the user, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Unopened vial: Store in a refrigerator between 2-8°C, protected from light. Do not freeze.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Octreotide solution for injection or concentrate for solution for infusion is filled into clear glass vials closed with rubber stoppers and sealed with aluminium flip-off caps fitted with plastic flip-off discs. The product is packaged in cardboard boxes.

Packs sizes of 1, 3, 5, 6, 10, 20 and 30 vials.

6.6 Special precautions for disposal

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 is not recommended.

If Octreotide has been diluted, the prepared solution may be kept at room temperature but should be administered within 24 hours of preparation.

Single use only.

Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road,

Hampden Park,

Eastbourne,

East Sussex BN22 9AG UNITED KINGDOM

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1257

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 23/12/2011

10 DATE OF REVISION OF THE TEXT

11/11/2014