1. Name Of The Medicinal Product
Octreotide 500 micrograms/ml solution for injection
2. Qualitative And Quantitative Composition
One ampoule contains octreotide acetate equivalent to 500 micrograms of octreotide (as octreotide acetate).
For full list of excipients, see Section 6.1.
3. Pharmaceutical Form
Solution for injection.
1ml ampoule containing clear colourless solution for injection.
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
Octreotide is not antitumour therapy and is not curative in these patients.
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
Route of administration
Subcutaneous or intravenous use.
4.2 Posology And Method Of Administration
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.
Acromegaly
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 2.5ng/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 12 months. Six-monthly monitoring may be necessary in those patients whose clinical and biochemical control is less 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 s.c. therefore, no dose adjustment of octreotide is necessary.
Use in patients with impaired hepatic function
In a study with octreotide administered s.c. and i.v. it was shown that the elimination capacity may be reduced in patients with liver cirrhosis, but not in patients with fatty liver disease. In patients with liver cirrhosis, an adjustment of the maintenance dose may therefore be necessary.
Use in the elderly
In elderly patients treated with octreotide, there is no evidence for reduced tolerability or altered dosage requirements.
Use in children
Experience with octreotide in children is very limited.
4.3 Contraindications
Known hypersensitivity to octreotide or to any component of the formulations (see 6.1 List of excipients).
4.4 Special Warnings And Precautions For Use
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.
Sudden escape of gastroenteropancreatic endocrine tumours from symptomatic control by octreotide may occur infrequently, with rapid recurrence of severe symptoms.
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.
Thyroid function should be monitored in patients receiving long-term octreotide therapy.
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).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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. carbamazepine, digoxin, warfarin and terfenadine).
4.6 Pregnancy And Lactation
Experience with octreotide in pregnant or nursing women is very limited, and they should therefore be given the drug only under compelling circumstances.
Women receiving treatment with octreotide should not breastfeed their infants.
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 main side-effects are local and gastrointestinal.
Body as a whole
Rare: hypersensitivity skin reactions; hair loss and isolated reports of anaphylactic reactions have been observed.
Cardiovascular system
Isolated cases of bradycardia.
Gastrointestinal system
Anorexia, nausea, vomiting, abdominal pain, abdominal bloating, flatulence, loose stools, diarrhoea and steatorrhea. Although measured faecal fate excretion may increase, there is no evidence to date that long-term treatment with octreotide has led to nutritional deficiency due to malabsorption. In rare instances, gastrointestinal side-effects may resemble acute intestinal obstruction with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. Occurrrence 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.
Hepatobiliary
Prolonged use of octreotide may result in gallstone formation (see 4.4 Special warnings and precautions for use), and 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.
There have been isolated reports of hepatic dysfunctions associated with octreotide administration. These consist of
• acute hepatitis, without cholestasis, where transaminase values have normalised on withdrawal of octreotide, or
• slow development of hyperbilirubinaemia in association with elevation of alkaline phosphatase, gamma-glutamyl transferase and, to a lesser extent, transaminases.
Pancreas
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 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.
Local reactions
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.
4.9 Overdose
Doses of up to 2000 microgrammes octreotide given as subcutaneous tid for several months have been well tolerated.
No life-threatening reactions have been reported after acute overdosage. The maximum single dose given to an adult so far has been 1 mg by intravenous bolus injection. The observed signs and symptoms were a brief drop in heart rate, facial flushing, abdominal cramps, diarrhoea, an empty feeling in the stomach and nausea, which resolved in 24 hours of drug administration.
One patient has been reported to have received an accidental overdosage of octreotide by continuous infusion (250 microgrammes per hour for forty eight hours instead of 25 microgrammes per hour). He experienced no side-effects.
The management of overdosage is symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antigrowth hormones (ATC code H01B C02).
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:
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.
5.2 Pharmacokinetic Properties
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.
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. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium acetate trihydrate
Glacial acetic acid
Sodium chloride
Water for injections
6.2 Incompatibilities
None known.
6.3 Shelf Life
36 months.
6.4 Special Precautions For Storage
For prolonged storage, ampoules should be stored between 2ºC and 8ºC. For day-to-day use they may be stored at room temperature for up to two weeks. Protect from light. Do not freeze.
6.5 Nature And Contents Of Container
1 ml ampoule of uncoloured glass containing clear colourless solution.
Boxes of 5 ampoules.
6.6 Special Precautions For Disposal And Other Handling
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.
If octreotide has been diluted, the prepared solution may be kept at room temperature but should be administered within 8 hours of preparation.
To reduce local discomfort, let the solution reach room temperature before injection. Avoid multiple injections at short intervals at the same site.
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.
7. Marketing Authorisation Holder
Sun Pharmaceuticals UK Ltd
1200 Century Way,
Thorpe Business Park,
Colton,
Leeds,
W Yorkshire,
LS15 8ZA
UK
8. Marketing Authorisation Number(S)
PL 24897/0003
9. Date Of First Authorisation/Renewal Of The Authorisation
12 May 2008
10. Date Of Revision Of The Text
April 2010
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