A review of long-term safety experience with products using OSM controlled-release technology yields a low incidence of clinically significant GI events. Properly prescribed, extended-release products provide substantial therapeutic and convenience benefits without additional risk.

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This 28-day study in rats evaluated the safety of melatonin delivered continuously subcutaneously by an ALZET Osmotic Pump. ALZET Osmotic Pumps 2ML4 continuously delivered 60 μ1/day of vehicle (polyethylene glycol 400), 0.03%, 0.3%, or 3% melatonin subcutaneously for 28 days to Sprague-Dawley rats (19/sex/group). The dose of melatonin delivered based on weekly group mean body weights (n = 10) was approximately 0.050,0.50, and 4.8 mg/kg day for the male groups and 0.074, 0.75, and 7.3 mg/kg day for the female groups. An additional group (19/sex) underwent surgery, but no osmotic pumps were implanted (sham control). No deaths or changes in clinical observations occurred that were attributed to melatonin. No drug effect occurred in body weights, hematology, clinical chemistry, urinalyses, or gross pathology. A dose-related trend of increasing serum melatonin concentrations occurred in males and females. In males, there was a trend toward decreasing serum prolactin concentrations with time at all levels of melatonin treatment. No difference in serum follicle-stimulating hormone (FSH) concentrations occurred between treated groups. Most of the samples were at the limit of detection for the serum luteinizing hormone (LH) assay (0.157 ng/ml). A dose-related increase occurred in urine 6-sulphatoxymelatonin (the primary metabolite) concentrations in melatonin-treated male and female groups. No treatment-related organ weight or histopathology changes were present in rats infused with 0.03% or 0.3% melatonin. Two of 10 males administered 3.0% melatonin had decreased testes weights and testicular degenerative changes composed of reduced or absent spermatogenesis, spermatidic giant cells, and edema. The cause of the observed testicular degenerative changes in the high-dose group and possible reversibility should be investigated in follow-up studies of longer duration.

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