General Information

Somatuline Depot (lanreotide acetate) is an injectable, sustained-release formulation of lanreotide, an octapeptide somatostatin analog that inhibits Insulin-like growth factor-1 (IGF-1) and growth hormone (GH).

Somatuline is specifically indicated for the long-term treatment of acromegalic patients who have had an inadequate response to surgery and/or radiotherapy, or for whom surgery and/or radiotherapy is not an option.

Mechanism of Action

Somatuline Depot (lanreotide acetate) is an injectable, sustained-release formulation of lanreotide, an octapeptide somatostatin analog that inhibits Insulin-like growth factor-1 (IGF-1). Lanreotide has a high affinity for human somatostatin receptors (SSTR) 2 and 5 and a reduced binding affinity for human SSTR1, 3 and 4. Activity at human SSTR 2 and 5 is the primary mechanism believed responsible for growth hormone inhibition. Like somatostatin, lanreotide is an inhibitor of various endocrine, neuroendocrine, exocrine and paracrine functions.

Side Effects

Adverse events associated with the use of Somatuline Depot may include, but are not limited to, the following:

• diarrhea
• abdominal pain
• nausea
• constipation
• flatulence
• vomiting
• loose stools
• cholelithiasis
• injection site reactions

Dosing/Administration

Somatuline is supplied in strengths of 60 mg, 90 mg and 120 mg designed for subcutaneous injection. The recommended initial dose of the drug in subjects with moderate and severe renal or moderate and severe hepatic impairment is 60 mg at four-week intervals for three months followed by dose adjustment as described below. The recommended initial dose of the drug for all other subjects is 90 mg at four-week intervals for three months. After three months the dosage may be adjusted as follows:

• GH >1 to = 2.5 ng/mL, IGF-1 normal and clinical symptoms controlled: maintain Somatuline Depot dose at 90 mg every four weeks.
• GH > 2.5 ng/mL, IGF-1 elevated and/or clinical symptoms uncontrolled, increase Somatuline Depot dose to 120 mg every four weeks.
• GH = 1 ng/mL, IGF-1 normal and clinical symptoms controlled: reduce Somatuline Depot dose to 60 mg every four weeks.

Thereafter the dose should be adjusted according to the response of the patient as measured by reduction in serum GH and /or IGF-1 levels; and/or changes in symptoms of acromegaly.

Clinical Trial Results

FDA approval of Somatuline Depot was based on the results of two clinical studies.
Study One
This one-year study consisted of a four-week, double-blind, placebo-controlled phase, a 16-week single-blind, fixed-dose phase and a 32-week open-label dose-titration phase. All the subjects who had received previous treatment with a somatostatin analog or a dopaminergic agonist were required to undergo a 12-week washout period. In the initial phase, 108 subjects were randomly allocated to receive a single deep subcutaneous injection of Somatuline Depot 60, 90 or 120 mg or placebo. Four weeks later, they entered a fixed dose phase where they received four injections of Somatuline Depot; this was completed by 105 subjects. This was followed by a dose-titration phase of eight injections for a total of 13 injections over 52 weeks (including the placebo phase). Injections were given at four-week intervals. The dose was titrated twice (every fourth injection), as needed. This phase was completed by 99 subjects. In the double-blind phase of the study, a total of 63 percent of the lanreotide treated subjects had a > 50 percent decrease in mean GH from baseline to week 4 including 52 percent, 44 percent and 90 percent of patients in the 60, 90 and 120 mg groups, respectively, compared to placebo (0 percent). In the fixed-dose phase at week 16, 72 percent of all lanreotide-treated subjects had a decrease from baseline in mean GH of > 50 percent including 68 percent, 64 percent and 84 percent of subjects in the 60, 90 and 120 mg lanreotide treatment groups, respectively. Efficacy achieved in the first 16 weeks was maintained throughout the trial duration.

Study Two
This 48-week, open-label, uncontrolled study enrolled 63 subjects with IGF-1 concentration = 1.3 times the upper limit of normal age range; of whom 57 completed treatment. Any subject who had received prior treatment with a somatostatin analog or dopaminergic agonist underwent a washout period of up to three months. The subjects entered a four-month fixed dose phase where they received four deep 90 mg subcutaneous injections of Somatuline at four-week intervals. They then entered into a dose-titration phase where the dose of Somatuline was adjusted according to GH and IGF-1 levels at the beginning of the dose titration phase and, if necessary, after another four injections. The subjects were titrated up to the maximum dose of 120 mg and could not titrate down again. After 48 weeks, 43 percent of the subjects achieved normal age-adjusted IGF-1 concentrations. The mean IGF-1 concentrations after treatment were 1.3 ± 0.7 times the upper limit of normal compared to 2.5 ± 1.1 times the upper limit of normal at baseline. The proportion of subjects with mean GH concentrations of < 2.5 ng/mL increased significantly from 35 percent to 77 percent after the fixed-dose phase and 85 percent at the end of the study. At the end of treatment 38 percent of the subjects had both normal IGF-1 concentrations and a GH concentration of less than or equal to 2.5 ng/mL and 27 percent had both normal IGF-1 concentrations and a GH concentration of <1 ng/mL.