Drug Information for Sandostatin LAR Depot (octreotide acetate for injectable suspension) (Novartis Pharmaceuticals Corporation): 12  CLINICAL PHARMACOLOGY

  • Sandostatin LAR Depot 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 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 4 weeks.

  • 12.1 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).

  • 12.2 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 (5)].

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

  • 12.3 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 nonlinear 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 (ta1/2 = 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.

    In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals.

    The half-life in renal-impaired patients was slightly longer than normal subjects (2.4-3.1 h versus 1.9 h). The clearance in renal-impaired patients was 7.3-8.8 L/h as compared to 8.3 L/h in healthy subjects. In patients with severe renal failure requiring dialysis, clearance was reduced to about half that found in healthy subjects (from approximately 10 L/h to 4.5 L/h).

    Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide half-life increasing to 3.7 h and total body clearance decreasing to 5.9 L/h, whereas patients with fatty liver disease showed half-life increasing to 3.4 h and total body clearance of 8.4 L/h. In normal subjects, octreotide half-life is 1.9 h and the clearance is 8.3 L/h which is comparable with the clearance in fatty-liver patients.

    Sandostatin LAR Depot

    The magnitude and duration of octreotide serum concentrations after an intramuscular injection of the long-acting depot formulation Sandostatin LAR Depot reflect the release of drug from the microsphere polymer matrix. Drug release is governed by the slow biodegration of the microspheres in the muscle, but once present in the systemic circulation, octreotide distributes and is eliminated according to its known pharmacokinetic properties which are as follows.

    After a single IM injection of the long-acting depot dosage form Sandostatin LAR Depot in healthy volunteer subjects, the serum octreotide concentration reached a transient initial peak of about 0.03 ng/mL/mg within 1 hour after administration progressively declining over the following 3-5 days to a nadir of <0.01 ng/mL/mg, then slowly increasing and reaching a plateau about 2-3 weeks postinjection. Plateau concentrations were maintained over a period of nearly 2-3 weeks, showing dose proportional peak concentrations of about 0.07 ng/mL/mg. After about 6 weeks postinjection, octreotide concentration slowly decreased, to <0.01 ng/mL/mg by Weeks 12 to 13, concomitant with the terminal degradation phase of the polymer matrix of the dosage form. The relative bioavailability of the long-acting release Sandostatin LAR Depot compared to immediate-release Sandostatin Injection solution given subcutaneously was 60%-63%.

    In patients with acromegaly, the octreotide concentrations after single doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot were dose proportional. The transient Day 1 peak, amounting to 0.3 ng/mL, 0.8 ng/mL, and 1.3 ng/mL, respectively, was followed by plateau concentrations of 0.5 ng/mL, 1.3 ng/mL, and 2.0 ng/mL, respectively, achieved about 3 weeks postinjection. These plateau concentrations were maintained for nearly 2 weeks.

    Following multiple doses of Sandostatin LAR Depot given every 4 weeks, steady-state octreotide serum concentrations were achieved after the third injection. Concentrations were dose proportional and higher by a factor of approximately 1.6 to 2.0 compared to the concentrations after a single dose. The steady-state octreotide concentrations were 1.2 ng/mL and 2.1 ng/mL, respectively, at trough and 1.6 ng/mL and 2.6 ng/mL, respectively, at peak with 20 mg and 30 mg Sandostatin LAR Depot given every 4 weeks. No accumulation of octreotide beyond that expected from the overlapping release profiles occurred over a duration of up to 28 monthly injections of Sandostatin LAR Depot. With the long-acting depot formulation Sandostatin LAR Depot administered IM every 4 weeks the peak-to-trough variation in octreotide concentrations ranged from 44%-68%, compared to the 163%-209% variation encountered with the daily subcutaneous three times daily regimen of Sandostatin Injection solution.

    In patients with carcinoid tumors, the mean octreotide concentrations after 6 doses of 10 mg, 20 mg, and 30 mg Sandostatin LAR Depot administered by IM injection every 4 weeks were 1.2 ng/mL, 2.5 ng/mL, and 4.2 ng/mL, respectively. Concentrations were dose proportional and steady-state concentrations were reached after 2 injections of 20 mg and 30 mg and after 3 injections of 10 mg.

    Sandostatin LAR Depot has not been studied in patients with renal impairment.

    Sandostatin LAR Depot has not been studied in patients with hepatic impairment.

  • Drug Information Provided by National Library of Medicine (NLM).