Stilamin (Somatostatin)

STILAMIN® Serono Somatostatin Treatment of Acute Variceal Bleeding

Action and Clinical

Somatostatin is a synthetic cyclic 14 amino acid peptide (identical in structure and activity to naturally occurring somatostatin) which decreases splanchnic blood flow and portal venous pressure in man, possibly through a direct action on the unstriated muscle cells mediated by a calcium-dependent mechanism. In anesthetized healthy volunteers, somatostatin–dosed as a 250 g i.v. bolus followed by a 250 g/hour continuous infusion–also reduced blood flow in the common hepatic artery (56%), in the splenic artery (26%) and in the upper and lower mesenteric branches. In cirrhotic patients, wedged hepatic pressure and estimated liver blood flow were decreased with the administration of somatostatin.:

Somatostatin is rapidly metabolized by the liver (plasma half-life of 1.1 to 3 minutes in healthy subjects) and cleared (50.3±7.0 mL/kg/min) from the body. Consequently, its pharmacological effects are transient, and a return to basal levels is generally seen shortly after the cessation of an i.v. infusion. In cirrhotic patients, the plasma half-life (1.2 to 4.8 minutes) approximates that of healthy volunteers while in patients with chronic renal failure, the plasma half-life is prolonged (2.6 to 4.9 minutes, see Precautions and Dosage). Somatostatin is excreted renally, with excretion 70% complete within 24 hours after dosing.

Indications And Clinical Uses:

For the symptomatic treatment of acute bleeding from esophageal varices. Other treatment options for long-term management of the condition may be considered if necessary, once initial control has been established.

Contra-Indications:

Cases of known hypersensitivity to the product, its excipients or recommended diluents.

Pregnancy and Lactation: The use of somatostatin in known or suspected pregnancy and during the immediate post partum period is contraindicated.

During preclinical studies in the rabbit, somatostatin doses of 0.2 mg/kg/day and higher were found to interfere with the early stages of embryonal development (e.g., implantation). Studies performed in pregnant women during labor indicated that somatostatin (500 g infused over 30 minutes) crossed the placental barrier, with effects on fetal levels of growth hormone and thyrotrophin.

In the absence of data concerning the effects of somatostatin on human pregnancy, its use is not recommended.

There is no information from animal or human studies concerning the passage of somatostatin in breast milk. As somatostatin has a wide variety of potential pharmacological effects, its use during lactation is contraindicated until further information can be obtained.

Warnings in Clinical States:

Somatostatin has an inhibitory effect on the secretion of insulin and glucagon. Therefore, at the outset of treatment, somatostatin can lead to a transient fall in blood glucose levels. Caution should therefore be used in administering the product to insulin-dependent diabetics in whom blood glucose should be measured every 3 to 4 hours. Simultaneous administration of insulin-requiring sugars should be avoided if possible. Insulin should be administered as necessary.

Children: There is no information concerning the use of somatostatin in children. Use in this patient population should only be considered if the potential benefits outweigh the possible risks.

Precautions:

General: As somatostatin has a short plasma half-life, it is essential that the infusion be maintained continuously once it has been initiated. In the event that any interruption in the infusion occurs, a repeat bolus dose may be given to the patient, followed by resumption of the continuous infusion (see Dosage).

Patients with Renal Disease: The plasma half-life of somatostatin is increased in patients with chronic renal disease, and its rate of clearance is reduced. Somatostatin should therefore be administered to such patients with caution.

Drug Interactions:

Somatostatin has been demonstrated to prolong or enhance the effects of barbiturates such as hexobarbital and pentetrazole, in preclinical studies. Caution should be used in administering such agents concomitantly with somatostatin.

The glucoregulatory properties of somatostatin may cause it to interfere with the insulin requirements of insulin-dependent diabetics (see Warnings).

Laboratory Tests: Somatostatin has produced transient hyperglycemia and thrombocytopenia in some patients (see Adverse Effects).

Adverse Reactions:

The adverse reactions which were reported by more than one patient during the clinical trials with the product in 278 patients included: nausea (4.0%), vomiting (2.1%), hyperglycemia (generally transient) (1.8%), pyrexia (1.8%), hypocalcemia (0.7%), headache (0.7%), thrombocytopenia (0.7%) and ventricular extrasystoles (0.7%).

Symptoms And Treatment Of Overdose:

Symptoms: Transient bradycardia and hypotension were observed in some preclinical studies and may be a sign of overdosage in humans. Cramping and vomiting have been reported as the result of an accidental overdosage with somatostatin.Treatment

Treatment: The infusion should be stopped immediately if overdosage is suspected. Given the short half-life of somatostatin, symptoms should resolve rapidly with the cessation of the infusion. Other treatment would consist of standard supportive measures until the symptoms have been resolved.

Dosage & Administration:

Somatostatin should be given as a slow 250 g i.v. bolus injection over 3 to 5 minutes, followed by a continuous infusion at a rate of 250 g/hr until bleeding from the varices has stopped (usually within 12 to 24 hours). Once bleeding has been controlled, it is recommended that the infusion be continued for at least another 48 to 72 hours, or out to a maximum of 120 hours to prevent recurrent bleeding.

The short plasma half-life of somatostatin makes it essential that the infusion be maintained continuously. It has therefore been the practice in some clinical trials to establish the continuous infusion line prior to administering the bolus dose to ensure that the administration of the drug is uninterrupted. If the continuous infusion is interrupted for any reason, a second bolus dose may be given to rapidly re-establish circulating levels of the drug.

Patients with decreased renal function should be closely monitored since the plasma half-life is prolonged.

Immediately prior to administration, the 250 g lyophilized product should be reconstituted with the sterile normal saline solution provided. Storage of the reconstituted product is not recommended.

The 3 mg lyophilized powder for continuous infusion should be reconstituted in either sterile normal (0.9%) saline or in 5% dextrose to provide sufficient solution for a 12-hour infusion of somatostatin at a rate of 250 g/hr (approximately 3.5 g/kg/hr). Once reconstituted it should be used within 24 hours and should be protected from light during this time.

Parenteral Products: Stilamin must be reconstituted before use.

Direct I.V. Injection: The 250 g ampul is accompanied by a 1 mL ampul of sterile, normal (0.9%) saline for reconstitution. Immediately before use, the sodium chloride solution should be added to the lyophilized material under aseptic conditions (creating a 250 g/mL solution) and swirled gently until all particles have been dissolved. Only clear solutions should be administered.

Continuous Infusion: The 3 mg ampul is not provided with diluent. It should be reconstituted with either sterile normal saline (0.9%) or in 5% dextrose prior to administration. The 3 mg ampul contains sufficient somatostatin to deliver a 12-hour continuous infusion at a rate of 250 g/hr. The volume of dilution will depend on the infusion system used and should be adjusted to ensure a continuous rate of infusion over 12 hours.

As with all parenteral drug products, i.v. admixtures should be inspected visually for clarity, particulate matter, precipitation, discoloration and leakage prior to administration whenever solution and container permit.

Stability and Storage Recommendations: The ampuls are stable when stored refrigerated (2 to 8°C). The product should be protected from light.

The Sodium Chloride diluent can be stored either at room temperature (15 to 30°C) or at refrigerated temperatures (2 to 8°C).

Reconstituted Solutions: Stilamin, reconstituted with sterile, normal (0.9%) saline or 5% dextrose to a concentration of 250 g/mL, is stable for 24 hours when refrigerated and protected from light.

Availability And Storage:

250 g: Each ampul of white, lyophilized, sterile, pyrogen-free powder contains: somatostatin 250 g (present as acetate hydrate) and mannitol 5 mg. Intended for reconstitution and administration as an i.v. bolus dose. Each ampul of Stilamin 250 g is accompanied by its diluent, a 3 mL ampul which contains 1 mL of sterile normal (0.9%) Sodium Chloride Injection. Cartons of 1 ampul of diluent and 1 ampul of somatostatin. Cartons of 5 ampuls of diluent and 5 ampuls of somatostatin.

3 mg: Each ampul of white, lyophilized, sterile, pyrogen-free powder contains: somatostatin 3 mg (present as acetate hydrate) and mannitol 5 mg. Intended for reconstitution and administration as a 12-hour continuous infusion (delivery 250 g/hour).

STILAMIN® Serono Somatostatin Treatment of Acute Variceal Bleeding

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