ral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycemic effects.
A small number of overdose cases have been reported in the post-marketing experience. In one case of acute overdose, a 3-year old patient experienced hypoglycemia after receiving one 4 mg dose of INCRELEX® (a 10-fold increase beyond the prescribed dose). The event resolved following treatment with IV glucose.
Long term overdosage with INCRELEX® may result in signs and symptoms of acromegaly.
11 DESCRIPTION
INCRELEX® (mecasermin [rDNA origin] injection) contains human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.
INCRELEX® is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multi-dose vial of INCRELEX® contains 10 mg per mL mecasermin, 9 mg per mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of ActionInsulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.
12.2 PharmacodynamicsThe following actions have been demonstrated for endogenous human IGF-1:
Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.
Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion.
12.3 Pharmacokinetics
Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of INCRELEX® given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.
Distribution – In blood, IGF |
