Octreotide 50 micrograms/1 ml Solution for Injection

Each 1 ml of Octreotide solution for injection contains 50 micrograms 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 a full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless.

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.

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 50 micrograms once or twice daily by subcutaneous injection is recommended. Depending on clinical response the dosage can be gradually increased to 100-200 micrograms three times daily. Under exceptional circumstances, higher doses may be necessary. Maintenance doses are variable. The recommended maximum daily dosage is 600 micrograms.

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 50 – 100 micrograms three times daily by subcutaneous. injection. For most patients the optimal daily dose is normally 200 – 300 micrograms daily. More than 1500 microgram 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 100 micrograms 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 children:

Experience with the use of Octreotide in children is limited.

Hypersensitivity to Octreotide or to any of the excipients of Octreotide (see section 6.1 Full list of excipients).

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.

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

Octreotide may reduce insulin requirements 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 should therefore be carefully monitored particularly at the initiation of treatment with Octreotide or when the dose is changed. Unstable blood sugar concentrations may be avoided by dividing the daily dose into several injections

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

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

The development of gallstones has been reported (estimated at between 15% and 30%) in association with Octreotide treatment. Ultrasonic examination for gallstones before, and at 6 to 12 month intervals during prolonged Octreotide treatment is recommended. The presence of gallstones in patients treated with Octreotide is usually asymptomatic; symptomatic stones should be treated in normal manner.

Liver function should be monitored during treatment with Octreotide.

Octreotide has been reported to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine. Combined treatment with Octreotide and cimetidine requires adjustment of doses.

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.

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

It is not known whether Octreotide passes into breast milk. Women receiving treatment with Octreotide should only breastfeed their infants if it is absolutely essential.

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

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), including isolated reports.

Further details are given after the table

(1) To reduce gastrointestinal adverse reactions, Octreotide should be administered between meals 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) 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.

(4) Gallstone formation with prolonged use (see 4.4. Special Warning and Precautions for Use).

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.

Doses of up to 2.0 mg Octreotide given three times a day via the subcutaneous route for several months have been well tolerated.

The maximum single dose so far given to an adult has been 1.0 mg as an intravenous bolus. The reversible symptoms of overdose observed were mild bradycardia, facial flushing, abdominal pains, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours after administration of the drug.

No potentially fatal reactions have been reported following acute overdose.

The management of overdosage should be symptomatic.

One patient has been reported to have received an accidental overdosage of Octreotide by continuous infusion (250 micrograms per hour for forty eight hours instead of 25 micrograms per hour). He experienced no side-effects.

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 thyrotropin-releasing 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).

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.

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.

Glacial acetic acid (pH adjustment),

Sodium acetate trihydrate (pH adjustment),

Sodium chloride,

Water for injections.

This medicinal product contains less than 1 mmol (23 mg) of sodium per 1 ml of solution, i.e. is essentially "sodium-free".

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

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 25ºC. 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 2ºC to 8ºC, unless dilution has taken place in controlled and validated aseptic conditions.

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

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

Storage conditions after dilution: please see section 6.3.

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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.

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

Single dose vials are for single use only.

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

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.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

PL 04515/0217

21^st May 2007

26^th June 2009