Sandostatin LAR® Depot (octreotide acetate for injectable suspension) is a long-acting dosage form consisting of microspheres of the biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer, containing octreotide. It maintains all of the clinical and pharmacological characteristics of the immediate-release dosage form Sandostatin® (octreotide acetate) Injection with the added feature of slow release of octreotide from the site of injection, reducing the need for frequent administration. This slow release occurs as the polymer biodegrades, primarily through hydrolysis. Sandostatin LAR® Depot is designed to be injected intramuscularly (intragluteally) once every four weeks.

Mechanism of Action

Octreotide exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.

By virtue of these pharmacological actions, octreotide has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea).

Pharmacodynamics

Octreotide substantially reduces and in many cases can normalize growth hormone and/or IGF-1 (somatomedin C) levels in patients with acromegaly.

Single doses of Sandostatin® Injection given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials the incidence of gallstone or biliary sludge formation was markedly increased [See WARNINGS and PRECAUTIONS].

Octreotide may cause clinically significant suppression of thyroid stimulating hormone (TSH).

Pharmacokinetics

Sandostatin Injection

According to data obtained with the immediate-release formulation, Sandostatin® Injection solution, after subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100 mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area-under-the-curve values were dose proportional both after subcutaneous or intravenous single doses up to 400 mcg and with multiple doses of 200 mcg three times daily (600 mcg/day). Clearance was reduced by about 66% suggesting non-linear kinetics of the drug at daily doses of 600 mcg/day compared to 150 mcg/day. The relative decrease in clearance with doses above 600 mcg/day is not defined.

In healthy volunteers the distribution of octreotide from plasma was rapid (tα_1/2 = 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L and the total body clearance was 10 L/h.

In blood, the distribution of octreotide 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.

The elimination of octreotide from plasma had an apparent half-life of 1.7 hours, compared with the 1-3 minutes with the natural hormone, somatostatin. The duration of action of subcutaneously administered Sandostatin® Injection solution is variable but extends up to 12 hours depending upon the type of tumor, necessitating multiple daily dosing with this immediate-release dosage form. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug.

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