, Volume 53, Issue 4, pp 681-699
Date: 23 Oct 2012

Octreotide Long-Acting Release (LAR)

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Summary

Synopsis

Octreotide is a somatostatin analogue: a long-acting release (LAR) formulation of octreotide is designed for once-monthly intramuscular administration. As with native somatostatin, octreotide LAR exerts potent inhibitory effects on the secretion of growth hormone and on various peptides of the gastroenteropancreatic endocrine system.

When patients with acromegaly who show a positive response to treatment with subcutaneous octreotide 300 to 600 µg/day are switched to octreotide LAR 20 or 30mg, the resulting decrease in growth hormone levels is stable and sustained.

Reductions in growth hormone levels to <5 µg/L for about 4 weeks are seen in 86 to 100% of patients, to <2 to 2.5 µg/L in 39 to 75% and to <1 µg/L in 24 to 40%. Levels of insulin-like growth factor- 1 (IGF- 1) decrease in parallel and are often normalised with repeated drug treatment. There is no evidence of tachyphylaxis with long term therapy (up to 34 months). Treatment with octreotide LAR improves facial appearance and soft tissue thickening, and eliminates or reduces the incidence of symptoms such as headache, fatigue, arthralgia and excessive perspiration. Tumour shrinkage has been noted in some, but not all, patients receiving octreotide LAR, although this has not been widely evaluated in clinical studies.

Overall, octreotide LAR is well tolerated, and the mild to moderate gastrointestinal events experienced by up to 50% of patients are of short duration and often subside with continued drug administration. The incidence of gallbladder abnormalities (sediment, sludge, microlithiasis and gallstones) increases in patients receiving long term therapy with subcutaneous octreotide, although most patients remain asymptomatic. The incidence of gallbladder abnormalities in patients receiving octreotide LAR compares favourably with that during subcutaneous administration. Glycaemic control is not usually altered during octreotide LAR treatment.

In summary, octreotide continues to be the principal pharmacological option for most patients with acromegaly. Octreotide LAR offers the convenience of once-monthly administration compared with daily subcutaneous drug administration. In addition, the good efficacy and tolerability profile of octreotide LAR should enhance patient compliance and acceptability of octreotide therapy and contribute to an improvement in patient quality of life.

Pharmacodynamic Properties

The pharmacodynamic properties of the long-acting release (LAR) formulation of octreotide do not appear to differ qualitatively from those of the subcutaneously administered formulation. A single intramuscular dose of octreotide LAR 20 or 30mg consistently reduced growth hormone levels to less than 5 µg/L for about 4 weeks; this was similar to reductions achieved with daily subcutaneous administration of octreotide (300 or 600 jig/day). The extent of growth hormone suppression was similar between the 2 doses of octreotide LAR but tended to persist for longer in patients who received 30mg (up to 60 days) than in those treated with 20mg (up to 28 days). Reductions were also seen in insulin-like growth factor-1 (IGF-1) levels. In general, doses of octreotide LAR ≤10mg were not as effective as 20 or 30mg.

Treatment with octreotide LAR for up to 1 year was not associated with receptor down-regulation or drug tachyphylaxis, nor did octreotide antibodies develop in patients over this period.

Octreotide inhibits the secretion of various endocrine hormones (such as insulin, glucagon, gastric inhibitory peptide, secretin, gastrin, neurotensin and motilin); it also influences intestinal motility, blood flow to the gut, and carbohydrate, electrolyte and water balance. Drug-induced impairment of gallbladder and sphincter of Oddi motility, inhibition of bile secretion, and altered hepatic and biliary acid composition are thought to contribute to the increased incidence of biliary tract dysfunction and gallstones in patients who receive long term octreotide therapy (see Tolerability summary below).

Untreated acromegaly results in myocardial hypertrophy, which leads to left ventricular dysfunction and heart failure. Subcutaneous octreotide 300 to 1500 µg/day induced rapid and sustained improvement in cardiac indices which included a decrease in left ventricular mass, decrease in heart rate, improved systolic and diastolic function indices, increase in stroke volume (in patients with congestive heart failure) and an increase in exercise capacity. Improvement in cardiac indices has not been reported with octreotide LAR, but would also be expected with this formulation.

Pharmacokinetic Properties

Octreotide LAR comprises a biodegradable polymer matrix which releases octreotide in a biphasic manner. An initial peak in serum octreotide concentrations seen within 1 hour of administration in patients with acromegaly is due to drug release from the surface of the microspheres. This peak coincides with an 8- to 12-hour period of growth hormone suppression (level not specified) which is similar to that seen after subcutaneous drug administration. Serum octreotide concentrations decline within 12 hours and remain low until 7 days after the initial injection; they then increase in a dose-dependent manner and plateau at about day 14. The plateau concentration remains stable until day 35 to 60 and then steadily declines.

In patients with acromegaly treated with octreotide LAR 20 or 30mg, therapeutic octreotide concentrations (usually 1 to 3 µg/L) are reached during the plateau phase and suppression of growth hormone secretion is maximal (levels reduced to between 2 and 5 µg/L). Octreotide concentrations reach steady-state in patients with acromegaly after 3 intramuscular injections of octreotide LAR at 4-week intervals.

Octreotide distributes mainly to the plasma and is approximately 65% protein bound. In patients with acromegaly, the volume of distribution is about 18 to 30L. The total body clearance rate in healthy individuals is about 9.6 L/h but is increased to 18 L/h in patients with acromegaly and decreases to 4.5 L/h in patients with chronic renal failure. About 11 to 32% of the drug is eliminated unchanged in the urine.

Therapeutic Use

The therapeutic efficacy of octreotide in the management of patients with acromegaly is well established. Repeated intramuscular administration of octreotide LAR (usually 20 or 30mg every 28 days) for up to 34 months effectively suppressed growth hormone levels to <5 µg/L in 86 to 100% of patients who had previously responded to subcutaneous octreotide 3 times daily. Growth hormone levels were further reduced to <2 or 2.5 µg/L in 39 to 75% and to <1 µg/L in 24 to 40% of these patients (n = 8 to 101). Similarly, serum levels of IGF-1 were markedly reduced from baseline over the same treatment period and normalised in 64 to 88% of patients in 3 of 4 trials.

After 7 injections of octreotide LAR 20 to 40mg (administered once every 4 weeks), symptoms such as headache, fatigue, carpal tunnel syndrome, paraesthesia and excessive perspiration disappeared in 47 to 81% of patients (n = 37 to 66) in the largest clinical trial. Similarly, up to 60% of patients in smaller trials became asymptomatic after treatment for ≤19 months. Facial appearance, soft tissue thickening, memory and concentration also improved. Tumour shrinkage was noted in 29 to 72% of patients treated long term with octreotide LAR 20 to 40mg (n = 7 to 32) who had previously responded to daily subcutaneous octreotide, but it was not clear whether this correlated with suppression of growth hormone or improvement in symptoms.

Tolerability

Overall, the tolerability of octreotide LAR resembles that of the subcutaneously administered formulation, although prospective comparative data are not available. Gastrointestinal adverse events such as abdominal pain, flatulence, diarrhoea, constipation, steatorrhoea, nausea and vomiting predominate after 1 to 3 doses of intramuscular octreotide LAR 10 to 30mg and occur in up to 50% of patients. However, these experiences are mild to moderate in severity and usually persist for only 1 to 4 days. Mild or moderate pain at the injection site was reported in up to 45% of patients, while erythema and swelling were less common; these events were generally of short duration.

Gallstones develop in fewer than 2% of patients treated with subcutaneous octreotide for less than 1 month; stones or sludge occur in approximately 20 to 50% of those who receive longer term therapy but most patients remain asymptomatic. Surgical treatment or bile acid therapy may be required in the approximately 1% of patients who become symptomatic. Many of the clinical trials with octreotide LAR reported gallbladder abnormalities (sediment, sludge, microlithiasis, gallstones), but at a lower frequency (<15%) and no patient required therapeutic intervention.

Impaired glucose tolerance was not reported in any of the clinical trials with octreotide LAR, nor did treatment result in significant changes in vital signs, haematology or blood chemistry.

Dosage and Administration

Intramuscular octreotide LAR is indicated for the treatment of acromegaly in patients who are adequately controlled on subcutaneous administration of octreotide, or in whom surgery, radiotherapy or dopamine agonist therapy is inappropriate or ineffective, or until the full effect of radiotherapy is realised.

Patients who respond well to subcutaneous octreotide 300 to 600 µg/day may be switched to octreotide LAR 20mg administered intramuscularly at 4-week intervals for 3 months. If clinical symptoms, and growth hormone and IGF-1 levels are not controlled satisfactorily within this period the dose may be increased to 30mg. Conversely, the dose of octreotide LAR may be reduced to 10mg in patients in whom treatment for 3 months consistently results in growth hormone levels <1 µg/L, normal IGF-1 levels and disappearance of most reversible clinical signs of acromegaly.

No dosage adjustment is necessary in elderly patients (e65 years) or those with impaired renal function (not defined) or liver cirrhosis. Baseline and periodic ultrasound examinations are recommended to monitor for gallbladder abnormalities in patients treated with octreotide LAR.

Various sections of the manuscript reviewed by: D.R. Abernethy, Departments of Medicine and Pharmacology, Georgetown University Medical Center, Washington, D.C., USA; M. Arosio, Institute of Endocrine Sciences, University of Milan, Milan, Italy; S. Ezzat, Department of Medicine, The Wellesley Hospital, Toronto, Ontario, Canada; S.K. Fløgstad, Section of Endocrinology, Medical Department B, Rikshospitalet, Oslo, Norway; A. Giustina, Department of Endocrinology, University of Brescia, Brescia, Italy; C. Jaffe, Division of Endocrinology and Metabolism, University of Michigan Medical Center, Ann Arbor, Michigan, USA; H. Ørskov, Institute of Experimental Clinical Research, University Hospital, Aarhus, Denmark; P.M. Stewart, Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, England; L. Weekes, NSW Therapeutic Assessment Group Incorporated, Darlinghurst, New South Wales, Australia.