Summary
Abstract
Octreotide long-acting release (LAR) is a somatostatin analogue designed for once monthly intramuscular injection. As with endogenous somatostatin, octreotide LAR inhibits secretion of growth hormone (GH) as well as various other peptide hormones.
In the treatment of acromegaly, octreotide LAR effectively controlled the secretion of GH and insulin-like growth factor-1 (IGF-1) in about 55–70% of patients (n > 100) who had previously been treated with somatostatin analogues, a similar degree of control to that observed with subcutaneous octreotide and lanreotide slow release (SR). Progressive control of serum levels of GH and IGF-1 was achieved with octreotide LAR in clinical studies of up to 4 years’ duration. In addition, primary therapy with octreotide LAR provided effective control of GH and IGF-1 secretion, particularly in patients with a pretreatment GH level <20 µg/ L.
The percentage of patients achieving a target serum GH level of <2–2.5 µg/L or normal IGF-1 levels was significantly greater with octreotide LAR 10, 20 or 30mg every 28 days than with lanreotide SR 30mg every 7–14 days in a large (n = 125) sequential, 6-month study, but was not significantly different between treatment groups in a small, randomised, nonblind, parallel group study of previously untreated patients. The volume of pituitary tumour shrinkage achieved with octreotide LAR or lanreotide SR was also similar (≈33% after 24 months). Acromegaly symptoms, such as headache, increased perspiration, paraesthesia, fatigue and osteoarthralgia were improved during treatment with octreotide LAR or lanreotide SR.
Overall, octreotide LAR is generally well tolerated by most patients. The incidence of gastrointestinal symptoms is about 30% but, in most cases, events are transient and mild to moderate. Gallbladder abnormalities (sediment, sludge, microlithiasis and gallstones) can occur, but only 1% have become symptomatic to date. The prevalence of biliary abnormalities did not change after switching from subcutaneous octreotide, or from lanreotide SR, to octreotide LAR. Glucose metabolism can be affected by octreotide LAR in some patients; about 15% become hyperglycaemic, usually mild in severity.
In summary, octreotide LAR controls GH and IGF-1 secretion in about 55–70% of patients with acromegaly. Octreotide LAR is administered intramuscularly every 28 days, offering improved patient compliance and convenience over three-times-daily subcutaneous octreotide. Long-term therapy provides progressive control of serum GH and IGF-1 levels, and is generally well tolerated by most patients. Thus, for the medical management of acromegaly, octreotide LAR is an effective, well tolerated and convenient treatment option.
Pharmacodynamic Properties
Octreotide long-acting release (LAR) is an octapeptide somatostatin analogue, with pharmacodynamic properties that are qualitatively similar to those of the subcutaneously administered formulation. A reduction in growth hormone (GH) levels from >5 µg/L, to <2 and <5 µg/L, respectively, was achieved in ≈29–61% and 87–100% of patients receiving a single intramuscular injection of octreotide LAR 20 or 30mg. The extent of GH suppression with octreotide LAR 20mg was similar to that with the 30mg dose, although the effect tended to persist for shorter periods. Octreotide LAR 10mg was generally not as effective as the higher doses. Marked reductions were also seen in insulin-like growth factor-1 (IGF-1) levels. Treatment with octreotide LAR for up to 1 year was not associated with receptor down-regulation, and antibody formation with octreotide LAR is rare.
Subcutaneous octreotide inhibits the secretion of various endocrine hormones (e.g. insulin, glucagon, gastric inhibitory peptide, secretin, gastrin, neurotensin and motilin) and decreases intestinal motility, blood flow to the gut, and carbohydrate, electrolyte and water absorption. With the exception of one small, crossover study in which glucose levels were significantly increased with octreotide LAR compared with baseline and lanreotide slow release (SR), glucose tolerance was not markedly impaired in patients receiving octreotide LAR. The increased incidence of biliary tract dysfunction and gallstones in patients with acromegaly receiving long-term octreotide LAR treatment appears largely related to suppression of cholecystokinin release and reduced gall-bladder emptying.
Octreotide LAR may arrest the progression of cardiomyopathy (as evidenced by decreased left ventricular mass index and increased left ventricular ejection fraction response at peak exercise) and improve atherosclerotic risk factors (as evidenced by a significant reduction in the intima media thickness of carotid arteries) in acromegaly by controlling the underlying disease, particularly in patients with an early diagnosis.
Pharmacokinetic Properties
Octreotide LAR comprises a biodegradable polymer matrix, from which octreotide is released in a biphasic manner. In patients with acromegaly, an initial peak in serum octreotide concentrations occurred within 1 hour of a single intramuscular dose of octreotide LAR 10–30mg, presumably from drug adsorbed to the carrier microspheres; this coincided with an 8- to 12-hour period of GH suppression (level not specified). Serum octreotide concentrations declined within 12 hours of drug administration, remaining subtherapeutic until day 7 before increasing in a dose-dependent manner to plateau at about day 14. The plateau concentration remained stable until day 35–60 and then steadily declined. Peak serum concentrations were dose dependent and were reached in 28–34 days. Octreotide concentrations reached steady state after three intramuscular injections of octreotide LAR at 4-week intervals.
Therapeutic drug concentrations (usually 1000–3000 ng/L) were maintained throughout the plateau phase in patients receiving octreotide LAR 20 or 30mg; suppression of GH secretion was maximal (levels reached 2–5 µg/L) during this period. Bioavailability after 20 or 30mg doses is 39% or 50% relative to the subcutaneous formulation.
Distributed mainly to the plasma, octreotide is 41–65% protein bound. In patients with acromegaly, the volume of distribution is 18–30L (after an intravenous dose of 25–200µg). Hepatic extraction is believed to be extensive (30–40%), and ≈11–32% of the administered drug is eliminated unchanged in the urine. The elimination half-life of octreotide is 1.7 hours. Total body clearance is ≈10 L/h in healthy volunteers, 18 L/h in patients with acromegaly and 4.5 L/h in patients with chronic renal failure.
Clinical Efficacy
In patients not previously medically treated, octreotide LAR 10, 20 or 30mg every 28 days for 2 years was associated with GH levels <2.5 µg/L in 50–76% of patients and normal IGF-1 levels in 50–71%. In patients who had previously shown sensitivity to therapy with subcutaneous octreotide and subsequently received octreotide LAR for 6–36 months, GH levels ≤2.5 µg/L were achieved in 50–79%, and normal IGF-1 levels in 53–88%. Compared with patients who underwent prior surgery, patients receiving primary therapy with octreotide LAR had similar levels of GH and IGF-1 at 24 months. Patients with a pretreatment GH level <20 µg/L were more likely to attain target GH levels during primary therapy with octreotide than those with higher baseline values.
Octreotide LAR 10, 20 or 30mg per month for 3 months further improved control of GH and IGF-1 levels over those achieved during prior therapy with lanreotide SR 30mg every 7–14 days for at least 3 months in a large, nonblind, sequential study (n = 107; no washout period between treatments). In a small 24-month, randomised, nonblind, parallel-design study of previously untreated patients (n = 20), the efficacy of intramuscular octreotide LAR 10, 20 or 30mg every 28 days or intramuscular lanreotide SR 30mg every 7–10 days was similar, as demonstrated by the lack of a significant difference in the percentage of patients with GH levels <2 µg/L (50% vs 58%) and normal IGF-1 levels (50% vs 67%). Tumour shrinkage after 24 months was similar in both treatment groups: 34.8% versus 30.0%. Symptoms of acromegaly, such as headache, increased perspiration, paraesthesia, fatigue and osteoarthralgia, were generally improved during both treatment regimens and the incidence did not change following a switch from lanreotide SR to octreotide LAR.
Octreotide LAR decreased serum levels of growth hormone and IGF-1 after the first injection and levels continued to decline throughout the entire treatment period in studies of up to 4 years’ duration. Symptoms of acromegaly showed further improvement after patients (n = 128) were switched from subcutaneous octreotide to octreotide LAR.
Tolerability
Octreotide LAR is generally well tolerated by most patients. The most common adverse events are gastrointestinal disturbances and injection site reactions, both of which are usually transient and mild to moderate in severity. About a third of patients receiving octreotide LAR experience diarrhoea, abdominal pain and/or flatulence. Injection site pain is dose-related and has been reported in about 9% of patients receiving octreotide LAR 20mg per month. Withdrawal of medication as a result of gastrointestinal or injection site events is rare.
Biliary abnormalities, including gallstones, microlithiasis, sediment, and sludge are associated with octreotide LAR therapy; however, to date, only 1% of patients have become symptomatic and require a cholycystectomy. The prevalence of biliary abnormalities did not change after switching from subcutaneous octreotide, or from lanreotide SR, to octreotide LAR.
Approximately 2% of patients with acromegaly treated with octreotide (subcutaneous or long-acting intramuscular) develop hypoglycaemia, and about 15% develop hyperglycaemia. In most cases, the hypo- or hyperglycaemia is mild. Although most clinical studies reported no change in vital signs during therapy with octreotide LAR, two trials reported a significant decrease in mean diastolic blood pressure within the normal range.
Dosage and Administration
Octreotide LAR is administered intramuscularly every 28 days for the long-term maintenance of patients with acromegaly who are adequately controlled on subcutaneous octreotide, and in those who are not eligible for surgery or have not responded adequately to surgery and/or radiotherapy. Vials containing active drug incorporated in microspheres should be mixed with diluent immediately prior to injection. Intragluteal injection sites should be rotated to avoid irritation.
Patients currently receiving subcutaneous octreotide can be switched directly to octreotide LAR 20mg every 28 days. Dosage should be reassessed after 3 months, based on clinical symptoms and serum GH and IGF-1 levels, and continued at 10, 20 or 30mg. Close monitoring of GH and IGF-1 levels is recommended.
In patients new to octreotide, it is recommended that therapy begin with the subcutaneous formulation to determine response and tolerance before starting therapy with octreotide LAR.
Ultrasound examination of the gallbladder is recommended at baseline and at 6-monthly intervals. Glucose tolerance and antidiabetic treatment should also be monitored regularly, with insulin dosage reductions likely in patients with type 1 diabetes mellitus. Concomitant administration of octreotide LAR with some oral drugs may affect their absorption.
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Various sections of the manuscript reviewed by: G. Amato, Endocrinology Institute, Second University of Naples, Naples, Italy; N.R. Biermasz, Department of Metabolism and Endocrinolgy, Leiden University Medical Center, Leiden, The Netherlands; R. Cozzi, Division of Endocrinology, Niguarda Hospital, Milan, Italy; M. Doga, Department of Internal Medicine, University of Brescia, Brescia, Italy; S. Ezzat, Department of Endocrinolgy, University of Toronto, Toronto, Ontario, Canada; D. Ferone, Department of Endocrinological and Metabolic Sciences, University of Genova, Genova, Italy; Z. Merza, Diabetes and Endocrine Centre, Northern General Hospital, Sheffield, UK; P. Stewart, Department of Medicine, University of Birmingham, Birmingham, UK.
Data Selection
Sources: Medical literature published in any language since 1997 on octreotide, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘octreotide’ and (‘LAR’ or ‘long-acting’). EMBASE search terms were ‘octreotide’ and (‘LAR’ or ‘long acting’). AdisBase search terms were ‘octreotide’ and (‘LAR’ or ‘long-acting' or ‘once-monthly’). Searches were last updated 8 September 2003.
Selection: Studies in patients with acromegaly who received octreotide LAR. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Acromegaly, octreotide, octreotide long-acting release, pharmacodynamics, pharmacokinetics, somatostatin analogues, therapeutic use.
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McKeage, K., Cheer, S. & Wagstaff, A.J. Octreotide Long-Acting Release (LAR). Drugs 63, 2473–2499 (2003). https://doi.org/10.2165/00003495-200363220-00014
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DOI: https://doi.org/10.2165/00003495-200363220-00014