SANDOSTATIN

(Novartis)

Composition:

Octreotide.

Description:

Sandostatin is octreotide, a synthetic octapeptide analogue of somatostatin. MW: 1019.3 (free peptide)

Excipients: lactic acid, mannitol, sodium bicarbonate, water for injections.

Pharmacology:

Pharmacodynamics: Sandostatin is a synthetic octapeptide analogue of naturally occurring somatostatin with similar pharmacological effects, but with a considerably prolonged duration of action. It inhibits the secretion of serotonin and the gastro-entero-pancreatic peptides: gastrin, vasoactive intestinal peptide, insulin, glucagon, secretin, motilin, and pancreatic polypeptide, and of growth hormone (GH). Sandostatin, like somatostatin, decreases splanchnic blood flow.

In animals, Sandostatin is a more potent inhibitor of growth hormone, glucagon and insulin release than somatostatin with greater selectivity for GH- and glucagon-suppression. Chronic administration (26 weeks) of doses up to 1 mg/kg a day (given intraperitoneally) in the rat and up to 0.5 mg/kg a day (given intravenously) in the dog is well tolerated.

In healthy subjects Sandostatin has been shown to inhibit:

* release of growth hormone (GH) stimulated by arginine, exercise and insulin-induced hypoglycaemia

* postprandial release of insulin, glucagon, gastrin, other peptides of the GEP system, and arginine-stimulated release of insulin and glucagon

* thyrotropin releasing hormone (TRH) stimulated release of thyroid stimulating hormone (TSH).

In acromegalic patients (including those who have failed to respond to surgery, radiation or dopamine agonist treatment) Sandostatin lowers plasma levels of growth hormone and/or Somatomedin-C. A reduction in plasma GH (by 50% or more) occurs in almost all patients, and normalisation (plasma GH < 5 ng/mL) can be achieved in about half of the cases. Most patients with symptoms such as headache, skin and soft tissue swelling, hyperhidrosis, arthralgia, paraesthesia report a reduction in these symptoms. In patients with a large pituitary adenoma, Sandostatin treatment may result in some shrinkage of the tumour mass.

In patients with tumours of the gastro-entero-pancreatic endocrine system, Sandostatin, because of its diverse endocrine effects, modifies different clinical features. Clinical improvement and symptomatic benefit occur in patients who have severe symptoms related to their tumours despite previous therapies which include surgery, hepatic artery embolisation and various chemotherapies, e.g. streptozotocin and 5-fluorouracil.

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

Sandostatin's effects in the different tumour types are as follows:

Carcinoid tumours: Administration of Sandostatin may result in improvement of symptoms, particularly of flush episodes and severe diarrhoea. In some cases this is accompanied by a fall in plasma serotonin and reduced urinary excretion of 5-hydroxyindole acetic acid. In the event of no beneficial response to Sandostatin treatment, continuation of therapy beyond one week is not recommended, although in non-responders no serious sustained adverse drug effects have been reported.

Vasoactive intestinal peptide secreting tumours (VIPomas):

The biochemical characteristic of these tumours is overproduction of vasoactive intestinal peptide (VIP). In most cases, administration of Sandostatin 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. In some patients, computer tomography scanning suggests 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.

A large multi-centre study in patients with acute bleeding due to gastric or duodenal ulcer showed no benefit of Sandostatin over placebo in the control of haemorrhage.

Pharmacokinetics:

Absorption: After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.5 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. In a single dose study, the absolute bioavailability after s.c. administration was found to be significantly different for different doses, however the interindividual variability was large. Relative to an equivalent intravenous dose, the bioavailability of a subcutaneous dose was estimated to be 80-135%. This was established based on the respective plasma concentrations determined by a radioimmunoassay. Peak concentrations and area under the curve values were dose proportional both after s.c. or i.v. single doses up to 400 mcg and with multiple doses of 200 mcg t.i.d. (600 mcg/day). Clearance was reduced by about 66% suggesting non-linear kinetics of the drug at daily doses of 600 mcg/day as compared to 150 mcg/day. The relative decrease in clearance with doses above 600 mcg/day is not defined.

Distribution: The distribution of octreotide from plasma was rapid (t1/2_{sa= 0.2 h) and the volume of distribution after i.v. dosing was estimated to be 0.27 L/kg body weight. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.}

Elimination: The elimination of octreotide from plasma had an apparent half-life of 1.5 hours compared with 1 to 3 minutes with the natural hormone. The duration of action of Sandostatin is variable but extends up to 12 hours depending upon the type of tumour. About 32% of the dose is excreted unchanged into the urine.

Effect of renal and hepatic dysfunction on pharmacokinetics: In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in normal subjects (from approximately 10 L/h to 4.5 L/h). The effect of hepatic diseases on the disposition of octreotide is unknown.

Indications:

For symptomatic control and reduction of growth hormone and Somatomedin-C plasma levels in patients with acromegaly, including those who are inadequately controlled by surgery, radiotherapy, or dopamine agonist treatment. Sandostatin treatment is also indicated in acromegalic patients unfit or unwilling to undergo surgery, or in the interim period until radiotherapy becomes fully effective.

For the relief of symptoms associated with:

* Carcinoid tumours with features of the carcinoid syndrome

* VIPomas

Sandostatin is not an antitumour therapy and is not curative in these patients.

For reduction of the incidence of complications following pancreatic surgery.

Contra-indications:

Hypersensitivity to octreotide or to any component of the formulation.

Precautions:

Development of gallstones: Development of gallstones has been reported in 10-20% of long-term recipients of Sandostatin. Ultrasonic examination of the gallbladder before and at 6 to 12 monthly intervals during Sandostatin therapy is therefore recommended. If gallstones do occur, they are usually asymptomatic; symptomatic stones should be treated either by dissolution therapy with bile acids or by surgery.

GH secreting pituitary tumours: As GH secreting pituitary tumours may sometimes expand, thereby 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.

Gastro-entero-pancreatic endocrine tumours: In the treatment of gastro-entero-pancreatic endocrine tumours sudden escape from symptomatic control by Sandostatin may occur infrequently, with rapid recurrence of severe symptoms.

Effects on glucose regulation: In patients with concomitant hypersecretion of insulin, Sandostatin, because of its greater relative potency in inhibiting secretion of growth hormone and glucagon than of insulin, and its shorter duration of action on inhibition of the latter, may increase the depth of, and prolong the duration of hypoglycaemia. Such patients should be closely observed on introduction of Sandostatin therapy and at each change of dosage. Marked fluctuations of blood glucose concentration may possibly be reduced by more frequent administration of Sandostatin.

Patients with type I diabetes mellitus requiring insulin therapy may have their insulin requirements reduced by administration of Sandostatin. In non-diabetic patients and patients with type II diabetes mellitus who have partially intact insulin reserves, Sandostatin administration can result in prandial increases in glycaemia (see Adverse Reactions).

Sandostatin administration to patients who have concomitant bleeding gastro-oesophageal varices due to underlying hepatic cirrhosis increases the risk of development of insulin-dependent diabetes or of changes in insulin requirements in the presence of pre-existing diabetes. Therefore, appropriate monitoring of blood glucose levels is mandatory.

Use in patients with impaired hepatic function: In patients with liver cirrhosis, the half-life of the drug may be increased. If this occurs, adjustment of the maintenance dose may be considered.

Carcinogenicity: In repeat dose toxicity studies in rats of 52 weeks duration and longer, predominantly in males, sarcomas were noted at the subcutaneous injection site of octreotide in an acidic vehicle and at a lower incidence with the acidic vehicle alone. These did not occur in a mouse carcinogenicity study, nor did hyperplastic or neoplastic lesions occur at the subcutaneous injection site in a 52-week dog toxicity study. The 116-week rat carcinogenicity study also revealed uterine endometrial adenocarcinomas, their incidence reaching statistical significance at the highest dose of 1.25 mg/kg per day. There have been no reports of tumour formation at the injection sites in patients treated for up to 15 years with Sandostatin. All information available at present indicates that the finding of injection site sarcomas in rats is species-specific and has no significance for the use of the drug in humans. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumours were associated with oestrogen dominance in the aged female rats which does not occur in humans.

Use in Pregnancy:

Category C. Reproduction studies have been performed in rats and rabbits at doses up to 1 mg/kg and have revealed no evidence of any adverse effect of Sandostatin on fertility or morphogenesis. Foetal and post-natal growth retardation was seen in rats, probably due to suppression of growth hormone. No adequate and well controlled studies have been performed in pregnant women. Therefore, this drug should be used in pregnancy only if clearly needed.

Australian categorisation definition of:

Category C:

Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects maybe reversible. Accompanying text above should be consulted for further details.

Use in Lactation:

Experience with Sandostatin in nursing women is not available. In such patients the drug should be used only under compelling circumstances.

Interactions with Other Drugs:

Many patients with carcinoid syndrome or VIPomas being treated with Sandostatin have also been, or are being, treated with many other drugs to control the symptomatology or progression of the disease, including chemotherapeutic agents, H₂ antagonists, antimotility agents, drugs affecting glycaemic states, solutions for electrolyte and fluid support or hyperalimentation, antihypertensive diuretics, and anti-diarrhoeal agents.

Sandostatin has been reported to produce a reduction in the intestinal absorption of cyclosporin, and a delay in that of cimetidine.

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, possibly due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs which are mainly metabolised by CYP3A4 and which have a low therapeutic index should be used with caution.

Since Sandostatin has also been associated with alterations in nutrient absorption, its effect on absorption of any orally administered drugs should be carefully considered.

Where symptoms are severe and Sandostatin therapy is added to other therapies used to control glycaemic states such as sulphonylureas, insulin, diazoxide, and to beta blockers or agents for the control of fluid and electrolyte balance, patients must be monitored closely and adjustment made in the other therapies as the symptoms of the disease are controlled. Evidence currently available suggests these imbalances in fluid and electrolytes or glycaemic states are secondary to correction of pre-existing abnormalities and not to a direct metabolic action of Sandostatin. Adjustment of the dosage of drugs, such as insulin, affecting glucose metabolism may be required following initiation of Sandostatin therapy in patients with diabetes (see Precautions - Effects on glucose regulation).

Adverse Reactions:

The main side effects encountered with Sandostatin administration 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 or by injecting a smaller volume using a more concentrated solution.

Gastrointestinal side effects include anorexia, nausea, vomiting, crampy abdominal pain, abdominal bloating, flatulence, loose stools, diarrhoea, and steatorrhoea. Although measured faecal fat excretion may increase, there is no evidence to date that long-term treatment with Sandostatin has lead 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. Occurrence of gastrointestinal side effects may be reduced by avoiding meals around the time of Sandostatin administration, that is, by injecting between meals or on retiring to bed.

Because of its inhibitory action on growth hormone, glucagon and insulin release, Sandostatin may affect glucose regulation (see Precautions) and impair postprandial glucose tolerance. In some instances, with chronic administration, a state of persistent hyperglycaemia may be induced.

Other reactions that occur less frequently include headache, dizziness/light-headedness, fatigue, asthenia/weakness, flushing, oedema, hair loss and hypoglycaemia.

One case of clinical hypothyroidism has been reported in a patient who had received 1500 mcg Sandostatin daily for 19 months.

There have been isolated reports of hepatic or biliary dysfunctions associated with Sandostatin administration. These consist of the following:

* acute hepatitis without cholestasis where normalisation of transaminase values on withdrawal of Sandostatin has occurred.

* the slow development of hyperbilirubinaemia in association with elevation of alkaline phosphatase, gamma glutamyl transferase and, to a lesser extent, transaminases.

* gallstone formation (see Precautions).

Acute pancreatitis has been reported in rare instances. Generally, the effect is seen within the first hours or days of Sandostatin treatment and resolves on withdrawal of the drug. In addition, pancreatitis may develop in patients on long-term Sandostatin treatment who develop gallstones.

Rare cases of hypersensitivity skin reactions and very rare cases of anaphylactic reactions have been reported. Bradycardia has been reported very rarely.

Dosage and Administration:

Acromegaly: Initially 0.05-0.1 mg by subcutaneous injection every 8 or 12 hours. Dosage adjustment should be based on monthly assessment of GH levels and on clinical symptoms, and on tolerability. In most patients the optimal daily dose will be 0.2 to 0.3 mg. A maximum dose of 1.5 mg per day should not be exceeded.

If no relevant reduction of GH levels and no improvement of clinical symptoms have been achieved within three months of starting treatment with Sandostatin, therapy should be discontinued.

Gastro-entero-pancreatic endocrine tumours: Initially 0.05 mg once or twice daily by subcutaneous injection. Depending on clinical response, the effect on levels of circulating tumour products, and on tolerability, dosage can be gradually increased to 0.2 mg 3 times daily. Under exceptional circumstances higher doses may be required, however experience with doses above 750 mcg per day is limited. Maintenance doses can be variable, depending on differences in tumour activity and rate of progression.

Complications following pancreatic surgery: 0.1 mg three times daily by subcutaneous injection for seven consecutive days, starting on the day of operation at least one hour before laparotomy.

Administration of Sandostatin:

* Patients who are to self-administer the drug by subcutaneous injection must receive precise directions from the physician or the nurse.

* To reduce local discomfort, it is recommended that the solution reaches room temperature before injection. Multiple injections at short intervals at the same site should be avoided.

* Ampoules should be opened just prior to administration and any unused portion discarded.

* Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration. Do not use if particulates and/or discolouration are observed.

Use in the elderly: In elderly patients treated with Sandostatin, there was no evidence for reduced tolerability or altered dosage requirements.

Use in children: Experience with Sandostatin in children is very limited.

Overdosage:

Symptoms: No life-threatening reactions have been reported after acute overdosage. The maximum single dose so far given to an adult has been 1.0 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 within twenty-four hours of drug administration.

One patient has been reported to have received an accidental overdosage of Sandostatin by continuous infusion (0.25 mg per hour for forty-eight hours instead of 0.025 mg per hour). He experienced no side effects.

Treatment: The management of overdosage is symptomatic.

Pack:

Ampoules: 0.05 mg in 1 mL - box of 5; 0.1 mg in 1 mL - box of 5; 0.5 mg in 1 mL - box of 5.

Sandostatin 0.05 mg ampoule AUST R 42192

Sandostatin 0.1 mg ampoule AUST R 42193

Sandostatin 0.5 mg ampoule AUST R 42191

Storage:

Store at 2-8°C (Refrigerate. Do not freeze). Protect from light. For day-to-day use Sandostatin may be stored at room temperature (below 30°C) for up to 2 weeks. Any ampoules unused after this period out of the refrigerator should be discarded.

All States and A.C.T. - S.4.

TGA approved: 17 March 1994

Date of most recent amendment: 17 October 2000