SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Octreotide 0.5 mg/1 ml Solution for Injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of Octreotide solution for injection contains 0.5 mg of Octreotide as Octreotide acetate.

Octreotide solutions for injection contain less than 1 mmol (23 mg) of sodium per 1 ml of solution (i.e. essentially "sodium-free").

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the relief of symptoms associated with gastroenteropancreatic tumours (GEP tumours) including:

•    Carcinoid tumours with features of carcinoid syndrome

•    VIPomas

•    Glucagonomas

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

Acromegaly:

For symptomatic control and reduction of growth hormone (GH) and Insulin-like growth factor number-1 (IGF-1) plasma 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 surgery becomes effective.

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

Evidence from short term studies demonstrates 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

Administration by the subcutaneous route:

Octreotide should be administered by the subcutaneous route without reconstitution or dilution.

Administration by the intravenous route:

GEP tumours where a rapid response is needed (i.v. administration as a bolus): Octreotide should be diluted with 0.9% (w/v) Sodium Chloride solution for injection at a ratio not exceeding 1:100. Dilution with Glucose solution is not recommended.

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

Octreotide injection should be inspected prior to administration and only clear solutions without particles should be used.

GEP tumours:

Initially a dose of 0.05 mg once or twice daily by subcutaneous injection is recommended. Depending on clinical response the dosage can be gradually increased to 0.1-0.2 mg three times daily. Under exceptional circumstances, higher doses may be necessary. Maintenance doses are variable. The recommended maximum daily dosage is 0.6 mg.

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 through ECG.

In carcinoid tumours, if there is no beneficial response with the maximum tolerated dose of Octreotide within a week, the therapy should be discontinued.

Acromegaly:

Initially doses of 0.05-0.1 mg three times daily by subcutaneous injection.

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. Dose adjustment should be made based on monthly measurements of the amount of circulating growth hormones (GH or IGF-1), changes to the clinical picture and possible adverse events.

If no significant reduction of growth hormone (GH) levels and no improvement of clinical symptoms have been achieved within three months of starting treatment with Octreotide, therapy should be discontinued.

Prevention of complications following pancreatic surgery:

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

Use in patients with renal insufficiency:

Renal insufficiency 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 hepatic insufficiency:

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

Use in the elderly:

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

Use in paediatric population:

The safety and efficacy of Octreotide in patients younger than 18 years have not been established.

4.3    Contraindications

Hypersensitivity to Octreotide or to any of the excipients of Octreotide listed in section 6.1.

4.4    Special warnings and precautions for use General

Octreotide solutions for injection contain less than 1 mmol (23 mg) of sodium per 1 ml of solution (i.e. essentially "sodium-free").

Octreotide should only be used under specialist hospital supervision with appropriate facilities available for diagnosis and evaluation of response.

As growth hormone secreting pituitary tumours may sometimes expand, causing serious complications (e.g. visual field defect), it is essential that all patients be carefully monitored. If evidence of tumour expansion appears, alternative procedures should be considered.

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, Fertility, pregnancy, and lactation.

Thyroid function (TSH and thyroid hormone levels) should be monitored in patients receiving long-term Octreotide therapy.

Hepatic function should be monitored during treatment with octreotide. In patients with cirrhosis dosage adjustment may be necessary (see section 4.2. Posology and Method of Administration).

GEP endocrine tumours

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

Cardiovascular related events

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

Glucose metabolism

Because of its inhibitory action on growth hormone, glucagon, and insulin release, octreotide 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.

Octreotide may increase the depth and prolong the duration of hypoglycaemia in patients with insulinoma. This is because Octreotide is relatively more potent in inhibiting growth factor hormone and glucogon 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 administering lower but more frequent doses of octreotide.

Octreotide may reduce insulin requirements or oral hypoglycaemic in patients receiving treatment for type I diabetes mellitus. In non-diabetics and type II diabetics with partially intact insulin reserves, Octreotide administration can result in prandial increases in glycaemia.

Blood glucose levels and antidiabetic treatment should therefore be carefully monitored particularly at the initiation of treatment with Octreotide or when the dose is changed.

Gallbladder and related events

Octreotide exerts an inhibiting effect on gallbladder motility, bile acid secretion, and bile flow, and the associated development of gallstones has been reported (estimated at between 15% and 30%) in association with Octreotide treatment. The prevalence in the general population is 5 to 20%. Ultrasonic examination for gallstones before long-term treatment with Octreotide and thereafter with an interval of about 6 months is recommended. The presence of gallstones in patients treated with Octreotide is usually asymptomatic; symptomatic stones should be treated in the normal manner.

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 is mandatory.

Local Site reactions

In a 52-week toxicity study in rats, predominantly in males, sarcomas were noted at the subcutaneous injection site only at the highest dose (about 40 times the maximum human dose). No hyperplastic or neoplastic lesions occurred at the subcutaneous 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 Bi₂ 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

Ciclosporin: Octreotide has been reported to reduce the intestinal absorption of ciclosporin. Ciclosporin levels should be monitored and the dose should be increased if necessary.

Cimetidine: Octreotide has been reported to delay the absorption of cimetidine and the dose of cimetidine may need to be adjusted.

Concomitant administration of Octreotide and bromocriptine increases the bioavailability of bromocriptine.

Limited published data indicate that somatostatin analogs 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. quinine, terfenadine, carbamazepine, digoxin, warfarin) should therefore be used with caution.

Octreotide has been shown to decrease hepatic blood flow by about 30%. Thus, the risk for interactions with substances for which metabolism is dependent on liver blood flow should be considered.

4.6 Fertility, pregnancy and lactation

Fertility

There is no data regarding treatment with octreotide and its effects on fertility. Pregnancy

Pregnant women should only be prescribed octreotide under compelling circumstances (see also section 4.4, Special warnings and precautions for use).

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.

There are no adequate and well-controlled studies of use of octreotide in pregnant women. In the post-marketing experience data are on 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 0.1-0.3 mg/day of octreotide s.c.. In approximately two-thirds cases with known outcome, the women elected to continue octreotide therapy during their pregnancies.

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

The medicinal product should only be administered to these patients if circumstances make it clearly necessary.

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. There was no indication of direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

The potential risk for humans is unknown.

Breastfeeding

It is not known whether Octreotide passes into human breast milk. Women receiving treatment with Octreotide should only breastfeed their infants if it is clearly necessary. Animal studies have shown excretion of octreotide in breast milk.

4.7 Effects on ability to drive and use machines

No studies on the effects of Octreotide on the ability to drive and use machines have been performed.

4.8 Undesirable effects

The most frequently reported adverse reactions with octreotide treatment include metabolism and nutrition disorders, nervous system disorders, gastrointestinal disorders, hepatobiliary disorders, and general and administration site 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, localized 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.

Administration/injection site reactions characterised by pain, or a sensation of stinging, tingling, or burning at the site of subcutaneous injection, with redness and swelling, have been reported, but rarely last 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.

Although measured faecal fat excretion may increase, there is no evidence to date that longterm 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 very rare instances, acute pancreatitis has been reported; generally, this effect is seen within the first hours or days of octreotide subcutaneous treatment and resolves on withdrawal of the drug. In addition, cholelithiasis-induced pancreatitis has been reported for patients on long-term octreotide subcutaneous treatment.

Isolated reports of biliary colic have been reported following the abrupt withdrawal of octreotide 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 S-ST myocardial infarction wave changes. The relationship between octreotide and these events is not established because many of the patients have underlying cardiac diseases (see section 4.4 Special warnings and precautions for use).

The frequency of the undesirable effects listed below is defined using the following convention: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10,000, <1/1000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

The adverse drug reactions listed in Table 1, and the frequency of which they have been reported, have been collected from a combination of clinical studies (information per the Innovator SmPC).

Table 1: Summary Table of Adverse Reactions Reported With Octreotide derived from

clinical studies

MedDRA Organ System Class	Very com mon	Common	Uncommon	Rare	Very rare
Endocrine disorders		Hypothyro idism, Thyroid dysfunctio n (e.g. decreased TSH, decreased Total T4, and decreased Free T4).
Metabolism and nutrition disorders	Hyper glyca emia	Glucose tolerance impaired, Hypoglyca emia, anorexia.	Dehydratio n.
Nervous system disorders	Head ache	Dizziness
Cardiac disorders		Bradycardi a	Tachycardia
Respiratory, thoracic and mediastinal disorders		Dyspnoea

MedDRA Organ System Class	Very com mon	Common	Uncommon	Rare	Very rare
Gastrointesti nal disorders (1)	Abdo minal pain, Const ipatio n, Diarr hoea, Flatul ence, and Nause a.	Dyspepsia, Abdomina l bloating, Loose stools, Discoloura tion of faeces, Steatorrho ea, and Vomiting.		Acute pancreatitis, cases of cholelithiasis-induced pancreatitis (2), severe epigastric pain, Abdominal tenderness and guarding, and Acute intestinal obstruction.
Hepatobiliary disorders (3)	Chole lithias is.	Cholecysti tis, Biliary sludge, Hyperbilir ubinaemia, gallstone	Hepatic dysfunction
Skin and subcutaneous tissue disorders		Pruritus, Rash, and Alopecia.		Hypersensitivit y skin reactions, exanthema
General disorders and administratio n site conditions (4)	Inject ion site locali sed pain.
Investigations		Elevated transamina se levels

MedDRA	Very	Common	Uncommon	Rare	Very
Organ	com				rare
System Class	mon

(1)    To reduce gastrointestinal adverse reactions, Octreotide should be administered between n or before bed.

(2)    This effect is generally observed within the first hours or days of treatment with Octreotide and is reversible on discontinuation of the treatment.

(3)    Gallstone formation with prolonged use (see 4.4. Special Warnings and Precautions for Use)

(4)    Administration site effects are generally mild and of short duration. Local discomfort may be reduced by allowing the solution to reach room temperature before administration or by injecting a lower volume of a more concentrated solution.

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

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 Immune disorders

Anaphylaxis, allergy/hypersensitivity reactions.

Cardiac disorders

Arrhythmias.

Hepatobiliary disorders

Acute pancreatitis, acute hepatitis without cholestasis, cholestatic hepatitis.

Cholestasis, jaundice, cholestatic jaundice.

Skin and subcutaneous tissue disorders

Urticaria.

Investigations

Increased alkaline phosphatase levels, increased gamma glutamyl transferase levels.

4.9 Overdose

A limited number of accidental overdoses of octreotide in adults and children have been reported. In adults, the doses ranged from 2.4-6 mg/day administered by continuous infusion (0.1-0.25 mg/hour) or subcutaneously (1.5 mg 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 0.05-3 mg/day administered by continuous infusion (0.0021-0.5 mg/hour) or subcutaneously (0.05-0.1 mg). The only adverse event reported was mild hyperglycaemia.

No unexpected adverse events have been reported in cancer patients receiving

octreotide at doses of 3-30mg/day in divided doses subcutaneously.

Treatment

The management of overdosage should be symptomatic.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 8.1.3. Antigrowth Hormones. ATC code: H01CB02

Octreotide is a synthetic octapeptide analog of naturally occurring somatostatin with similar pharmacological effects, but with a longer duration of action. It inhibits pathologically increased secretion of growth hormone (GH) and of peptides and serotonin produced within the gastroenteropancreatic (GEP) endocrine system, stomach, intestine and pancreas (for example, gastrin, insulin and glucagon).

Octreotide gives symptomatic relief of the symptoms caused by functional tumours of the gastroenteropancreatic (GEP) endocrine system (stomach, intestine and pancreas) in patients whose symptoms have not been relieved by other forms of treatment such as surgery, hepatic artery embolisation or chemotherapy.

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

In healthy volunteers Octreotide has been shown to inhibit the release of GH stimulated by arginine, exercise and insulin-induced hypoglycaemia, and thyrotropinreleasing hormone (TRH)-stimulated release of thyroid-stimulating hormone (TSH).

Unlike somatostatin, Octreotide inhibits growth hormone (GH) and glucagon preferentially over insulin.

Discontinuation of treatment is not followed by a rebound effect with hypersecretion of hormones.

In patients with carcinoid tumours, Octreotide may result in relief of symptoms, particularly of flushing and diarrhoea. In many cases, this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid (5-HIAA).

In patients with VIPomas, the biochemical characteristic is overproduction of vasoactive intestinal peptide (VIP). In most cases, Octreotide alleviates 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, such as hypokalaemia. The need for administration of fluids and electrolytes is reduced. In some patients, computer tomography scanning reveals a slowing or arrest of progression of the tumour, or even tumour shrinkage, particularly of hepatic metastases. Clinical improvement is usually accompanied by a reduction in plasma VIP levels, which may fall into the normal reference range.

In glucagonomas, administration of Octreotide results in most cases in substantial improvement of the necrolytic migratory rash which is characteristic of this condition. The effect of Octreotide on the moderate 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 affected patients. 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.

In patients with acromegaly, Octreotide reduces GH and IGF-1 plasma levels. A GH reduction by around 50% or more occurs in over 90% of patients, and a reduction of plasma GH to < 5 ng/ml can be achieved in about half of the cases. In most patients, Octreotide significantly reduces clinical symptoms such as headache, swelling of skin and soft tissues, hyperhidrosis, arthralgia and paraesthesia. In patients with large volume pituitary adenomas, Octreotide may lead to shrinkage of the tumour mass.

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

5.2 Pharmacokinetic properties

Absorption

After subcutaneous administration, Octreotide is rapidly and completely absorbed. The peak plasma concentration is reached after 30 minutes.

Distribution

The volume of distribution is around 0.27 l/kg and the total body clearance is 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 administration is 100 minutes.

After intravenous administration, the elimination is biphasic with half-lives of 10 and 90 minutes. Most of the administered dose is eliminated in the faeces and approximately 32% is excreted in unchanged form in 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.

5.3 Preclinical safety data

Acute toxicity

Acute toxicity studies performed with Octreotide in the guinea-pig showed that LD50 is 72 mg/kg by IV and 470 mg/kg subcutaneously. In the mouse, LD50 was 18 mg/kg ( IV). Octreotide acetate was well tolerated by dogs that received up to 1 mg/kg by IV bolus.

Toxicity after repeated administration

A 26 weeks toxicity study in dogs, with IV doses up to 0.5 mg/kg, bid, showed progressive changes in acidophilic pituitary cells that contain prolactin. Further investigations showed that this variation was within the physiologic range and apparently not related to Octreotide administration. No significant changes were seen in plasma level of hormones. Rhesus monkey females receiving 0.5mg/kg bid for 3 weeks did not show pituitary changes nor changes in plasma levels of GH, prolactin or glucose.

Local tolerance

While acidic vehicle produced inflammation and fibroplasias in mouse after repeated injections, no evidence of Octreotide acetate causing hypersensitivity reactions was found in the guinea-pig model after intradermal administration.

In a toxicology study on predominantly male rats, sarcomas were observed at the subcutaneous injection site after 52 weeks, but only with the highest dose (around forty times the maximum dose used in humans). In a 52-week toxicology study in dogs, no hyperplastic or neoplastic lesions were observed at the subcutaneous injection site. No cases of tumour formation at the injection site have been reported in patients treated with Octreotide for periods of up to 15 years. All of the available information to date indicates that the results obtained in rats are species-specific and are not relevant for the use of the drug in humans.

Mutagenicity

Octreotide and/or its metabolites were without mutagenic potential in standard in vitro tests. An increase of chromosomic changes in V79 Chinese hamster cells was seen, in vitro, although only with high and cytotoxic concentrations. In human lymphocytes incubated with Octreotide acetate in vitro the chromosomal changes were not increased. Blastogenic activity in vivo (micronuclei test in guinea pigs) was not observed

Carcinogenicity

Studies with mice treated with SC Octreotide in daily doses up to 1.25 mg/kg of body weight, the presence of fibrosarcomas, after 52, 104 and 113/116 weeks was observed in some animals, mainly males. Local tumours in control group of mice also appeared, however the tumours were related to disorganized fibroplasias produced by irritant effects of the acid vehicle. In guinea-pigs that received daily SC injections of Octreotide in doses up to 2 mg/kg for 98 weeks, neoplastic lesions were not observed.

The mouse carcinogenicity study also revealed endometrial carcinomas, statistically significant for the highest SC dose of 1.25 mg/kg/day. This observation was associated with an increase in endometritis, a reduced number of luteal bodies, a reduction of breast adenomas and the presence of luminal dilation and glandular uterus, suggesting a hormonal imbalance. The available data indicates that the observed hormone-dependent tumours in mice are species specific and therefore not relevant for humans.

Reproduction toxicity

The fertility study as well as the studies of pre-, peri- and post-natal effects in rats did not reveal adverse events on the reproductive ability or on foetal development with doses up to 1 mg/kg/day SC. Some delay of offspring growth, which was transient and may be due the GH inhibition due to the excessive pharmacodynamic activity, was observed

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 due to the pharmacodynamic action of Octreotide, but there was no evidence of foetotoxic, teratogenic, or other reproductive effects.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Glacial acetic acid (pH adjustment), Sodium acetate trihydrate (pH adjustment), Sodium chloride,

Water for injections.

6.2 Incompatibilities

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

Shelf life

Medicinal product as packaged for sale: 2 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 0.9% sodium chloride solution for injection and stored in PVC bags or in polypropylene syringes has been demonstrated for seven days when stored at 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 and would normally not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Medicinal product as packaged for sale: store in a refrigerator (2°C - 8°C).

Do not freeze. Keep the vial in the outer carton in order to protect from light.

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

6.5 Nature and contents of container

2 ml Type I amber glass vials for injection, with a teflon-faced rubber stopper, aluminium seal and flip-off plastic cap, containing 1 ml of Octreotide solution for injection.

Packs of 5 and 30 vials containing 1 ml of solution for injection.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and handling

The vials for injection should be opened only immediately prior to use and any unused solution should be discarded.

Single dose vials (0.05 mg/ml, 0.1 mg/ml and 0.5 mg/ml injection) are for single use only.

To prevent contamination, it is recommended that the cap of the multidose vial (0.2 mg/ml) should be punctured no more than 10 times.

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

Prior to administration the solution should be inspected visually for changes of colour or solid particles.

Each vial contains a clear colourless solution, free from foreign matter.

It is not recommended to mix or dilute the Octreotide solutions for injection except with 0.9% Sodium Chloride solution.

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

MARKETING AUTHORISATION HOLDER

Mayne Pharma Plc

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

20/12/2012