OCTREOTIDE ACETATE
Description:
Octreotide is a synthetic octapeptide analogue of naturally occurring somatostatin and is available
as injection containing octreotide diacetate 50 mcg/ml and 100 mcg/ml, in I ml ampoules.
Clinical Pharmacology
Mechanism of Action:
Octreotide is a synthetic octapeptide analogue of naturally occurring somatostatin with similar
pharmacological effects, but with a longer duration of action. It inhibits the secretion of peptides
of the gastro-entero-pancreatic endocrine system and of growth hormone.
In animals, octreotide is a more potent inhibitor of growth hormone, glucagon and insulin release
than somatostatin with greater selectively for growth hormone and glucagon suppression.
In normal healthy subjects octreotide inhibits the release of growth hormone stimulated by
arginine, exercise and insulin-induced hypoglycemia; post-prandial release of insulin, glucagon,
gastrin, other peptides of the gastro-entero-pancreatic system; arginine-stimulated release of
insulin and glucagon and thyrotropin releasing hormone-stimulated release of thyroid stimulating
hormone.
Because of its diverse endocrine effects, octreotide modifies different clinical features in patients
with tumours of the gastro-entero-pancreatic endocrine system. Its effects in the different tumour
types are as follows:
Corcinoid tumours : It acts on the somatostatin receptors and induces splanchnic vasoconstriction
by:
a) direct effect on vascular smooth muscle
b) inhibition of release of several vasodilatory hormones e.g. glucagon. After Octride
administration, a reduction in the azygous blood flow has been observed.
Carcinoid tumours : Octride may improve symptoms, particularly flush and diarrhoea. In some
cases there is a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic
acid.
VIPomas : In most cases, Octride 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, e.g., Hypokalaemia, enabling enteral and parenteral fluid and
electrolyte supplementation to be withdrawn. A reduction in plasma VIP levels, often into the
normal reference range, usually accompanies clinical improvement.
Glucogonomas : Octride produces an improvement of the characteristic necrolytic migratory
rash in most patients. Its effect on the mild diabetes mellitus which frequently occurs is variable.
Octride produces improvement of diarrhoea, and hence weight gain in those patients affected.
Its administration often leads to an immediate reduction in plasma glucagon levels which is
generally not maintained long-term, despite continued symptomatic improvement.
Acromegaly : Octride lowers plasma levels of GH and/or somatomedin C. In most patients
Octride markedly reduces the clinical symptoms of the disease such as headache, skin and soft
tissue swelling, hyperhidrosis, arthralgia and paraesthesia.
Pharmacokinetics:
After subcutaneous injection, Octride is rapidly and completely absorbed, peak plasma concen-
trations are reached within 30 minutes. The elimination half-life after subcutaneous administra-
tion is 100 minutes. After intravenous injection the elimination is biphasic with half-lives of 10 and
90 minutes respectively. The volume of distribution is 0.27 I/kg and the total body clearance 160
ml/min. Plasma protein binding amounts to 65%. The amount of Octride bound to blood cells
is negligible.
Indications:
1. Octride is useful in the management of variceal bleeding. It is used as a STOP - GAP
therapy before sclerotherapy can be undertaken.
2. For the relief of symptoms associated with the gastro-entero-pancreatic endocrine tumours,
including carcinoid tumours with features of the carcinoid syndrome, VIPomas, and
glucagonomas.
Octride is not an antitumour therapy and is not curative in these patients.
3. For symptomatic control and reduction of growth hormone and somatomedin C plasma
levels in patients with acromegaly :
a) In short-term treatment prior to pituitary surgery, or
b) In long-term treatment in those who are inadequately controlled by pituitary surgery,
dopamine agonist treatment, radiotherapy, or in the interim period until radiotherapy
becomes fully effective.
Octride 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.
Contra-indications:
Hypersensitivity to the drug or its components.
Warnings and Precautions:
Sudden escape of gastro-entero-pancreatic endocrine tumours from symptomatic control by
Octride may occur infrequently, with rapid recurrence of severe symptoms.
Octride 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 Octride is given to
a patient with insulinoma, close observation is necessary on introduction of therapy and at each
change of dosage. Marked fluctuations of blood glucose concentration may be reduced by more
frequent administration of Octride.
Octride may reduce insulin or oral hypoglycaemic requirements in patients with diabetes mellitus.
Thyroid function should be monitored in patients receiving long-term Octride therapy.
Octride exerts an inhibitory effect on gallbladder motility, bile acid secretion and bile flow and
there is an acknowledged association with the development of gallstones. In some studies, an
incidence of upto 20% has been reported. Therefore ultrasound examination of the gallbladder
is recommended before treatment is initiated and at 6 to 12 month intervals thereafter. 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.
Octride has been reported to reduce the intestinal absorption of cyclosporin and to delay that
of cimetidine.
Pregnancy and Lactation:
Experience with Octride in pregnant or nursing women is not available. Animal studies showed
transient growth retardation of offspring, possibly consequent upon the specific endocrine profiles
of the species tested. There was no evidence of foetotoxic, teratogenic or other reproduction
effects. Octride should be used during pregnancy only if the potential benefits clearly outweigh
the potential risks.
Women receiving treatment with Octride should not breast feed their infants.
Side effects:
The main side effects are local and gastrointestinal.
Local reactions include pain, a sensation of stinging, tingling or burning at the site of injection, with
redness and swelling. They rarely last more than fifteen minutes. Local discomfort may be
reduced by allowing the solution to reach room temperature before injection.
Gastrointestinal side effects include anorexia, nausea, vomiting, abdominal pain, abdominal bloating,
flatulence, loose stools, diarrhoea and steatorrhoea, there is no evidence to date that long-term
treatment with octreotide has led to nutritional deficience due to malabsorption. In rare instances,
gastrointestinal side effects may resemble acute intestinal obstruction with progressive abdominal
distention, severe epigastric pain, abdominal tenderness and guarding. Occurrence of gastrointestinal
side effects may be reduced by avoiding meals around the time of Octride administration, that
is by injecting between meals or on retiring to bed.
Formulation of gallstones has been reported in patients on long-term Octride treatment and
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.
Because of its inhibitory action on insulin release; Octride may impair postprandial glucose
tolerance. In rare instances, with chronic administration, a state of persistent hyperglycaemia may
be induced.
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.
Overdosage:
No life-threatening reactions have been reported after acute overdosage. The maximum single
dose so far given to an adult has been I 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, all of which resolved within twenty-four hours of drug
administration.
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.
The management of overdosage is symptomatic.