To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Humatrope Approved for Somatropin Deficiency Syndrome in Adults URL: http://www.pslgroup.com/dg/9E46.htm Doctor's Guide August 8, 1996
INDIANAPOLIS -- August 8, 1996 -- Eli Lilly and Company announced today that is has received U.S. Food and Drug Administration permission to market Humatrope(R) (somatropin (rDNA origin) for injection) for Somatropin Deficiency Syndrome (SDS) in adults. The agency's action makes Humatrope the first therapy available for U.S. adults who suffer from SDS, frequently associated with hypopituitarism. Humatrope is a synthetic human growth hormone (hGH) that has been used since 1987 as a replacement therapy for children who do not produce enough or any of their own hGH. The FDA cleared the new adult indication for Humatrope after reviewing clinical data from multinational studies that were submitted to the federal agency by Lilly in August 1995. "This new use for Humatrope is an example of how continued study of a drug can offer new hope to patients who before now had no therapeutic option for their disorder," said August M. Watanabe, M.D., executive vice president of science and technology for Lilly. SDS adults may have hypopituitarism as a result of pituitary tumors, trauma, or other pituitary disorders, or they may have been treated for growth hormone deficiency as children. Adults with SDS suffer from metabolic disorders that affect their physical mobility, socialization, and energy levels, as well as their life expectancy. Some epidemiologic studies have suggested that adults with SDS are at greater risk of cardiovascular disease than adults without the disorder. In clinical trials, Humatrope therapy improved some of the symptoms that SDS patients experienced. Humatrope therapy resulted in an increase in lean muscle mass, a decrease in body fat, an increase in exercise capacity, and normalization of low HDL cholesterol levels in SDS patients. Patients who developed SDS in adulthood also reported, in a general, health-related quality of life questionnaire (the Nottingham Health Profile), improvements in physical mobility and social isolation, two health-related domains measured by the Profile. An increase in another domain, energy level, was also reported by adult onset SDS patients after 18 months of Humatrope therapy. The data for patients who developed SDS in childhood did not reflect Nottingham Health Profile improvements. Early in clinical trials, SDS patients taking Humatrope experienced edema and peripheral edema more frequently than patients receiving placebo. Other signs and symptoms reported during therapy include edema, joint pains or disorders, back pain, headaches, muscle aches, hypertension and rhinitis. Many of the signs and symptoms reported during therapy, however, resolved either spontaneously or in response to dosage adjustments. Hypopituitary and somatropin deficient adults should consult with an endocrinologist regarding the potential benefits and risks of replacement therapy with Humatrope. Humatrope therapy would be a supplement to any other hormone replacement therapy that hypopituitary patients may already be receiving (for example, estrogen, thyroid or hydrocortisone). Humatrope already has been approved for somatropin replacement therapy in adults in several countries outside the United States -- Greece, New Zealand, Sweden, Denmark, France, Germany, Spain, the Netherlands, Mexico, the United Kingdom, Norway and Finland. The drug also has been approved to treat growth hormone deficiency in children and Turner Syndrome in many countries outside the United States. Lilly is a global research-based pharmaceutical corporation headquartered in Indianapolis, Ind., that is dedicated to creating and delivering superior health care solutions -- by combining pharmaceutical innovation, existing pharmaceutical technology, disease prevention and management and information technologies -- in order to provide customers worldwide with optimal clinical and economic outcomes. Endocrine diseases are one of five therapeutic areas in which the company is focusing its efforts. Full prescribing information for Humatrope(R) (somatropin (rDNA origin) for injection) will be faxed immediately upon request. Description: Humatrope (somatropin (rDNA origin) for injection)) is a polypeptide hormone of recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin. Humatrope is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone. Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution. Each vial of Humatrope contains 5 mg somatropin (15IU (see footnote) or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Phosphoric acid and/or sodium hydroxide may have been added at the time of manufacture to adjust the pH. This product is oxygen sensitive. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting solution. The diluent contains water for injection with 0.3% m-cresol as a preservative and 1.7% glycerin added at the time of manufacture. Humatrope is a highly purified preparation. The 1.7% glycerin content makes the reconstituted product nearly isotonic at a concentration of 2 mg of Humatrope/mL diluent. Reconstituted solutions have a pH of approximately 7.5. Clinical Pharmacology: General: Linear Growth -- Humatrope stimulates linear growth in pediatric patients who lack adequate normal endogenous growth hormone. In vitro, preclinical, and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. Treatment of growth hormone-deficient pediatric patients with Humatrope produces increased growth rate and IGF-I (Insulin-Like Growth Factor-I/Somatomedin-C) concentrations similar to those seen after therapy with human growth hormone of pituitary origin. In addition, the following actions have been demonstrated for Humatrope and/or human growth hormone of pituitary origin. A. Tissue Growth -- 1. Skeletal Growth: Humatrope stimulates skeletal growth in pediatric patients with growth hormone deficiency. The measurable increase in body length after administration of either Humatrope or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-I, which may play a role in skeletal growth, are low in the serum of growth hormone-deficient pediatric patients but increase during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations are also seen. 2. Cell Growth: It has been shown that there are fewer skeletal muscle cells in short-statured pediatric patients who lack endogenous growth hormone as compared with normal pediatric populations. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells. B. Protein Metabolism -- Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen. C. Carbohydrate Metabolism -- Pediatric patients with hypopituitarism sometimes experience fasting hypoglycemia that is improved by treatment with Humatrope. Large doses of human growth hormone may impair glucose tolerance. D. Lipid Metabolism -- In growth hormone-deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilization, reduction in body fat stores, and increased plasma fatty acids. E. Mineral Metabolism -- Retention of sodium, potassium, and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatrope or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatrope. Pharmacokinetics: Absorption -- Humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in adult volunteers. The absolute bioavailability of somatropin is 75% and 63% after subcutaneous and intramuscular administration, respectively. Distribution -- The volume of distribution of somatropin after intravenous injection is about 0.07 L/kg. Metabolism -- Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products of growth hormone is returned to the systemic circulation. In normal volunteers, mean clearance is 0.14 L/hr/kg. The mean half-life of intravenous somatropin is 0.36 hours, whereas subcutaneously and intramuscularly administered somatropin have mean half-lives of 3.8 and 4.9 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site. Excretion -- Urinary excretion of intact Humatrope has not been measured. Small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy. Special Populations: Geriatric -- The pharmacokinetics of Humatrope has not been studied in patients greater than 60 years of age. Pediatric -- The pharmacokinetics of Humatrope in pediatric patients is similar to adults. Gender -- No studies have been performed with Humatrope. The available literature indicates that the pharmacokinetics of growth hormone is similar in both men and women. Race -- No data are available. Renal, Hepatic insufficiency -- No studies have been performed with Humatrope. Table 1, entitled Summary of Somatropin Parameters in the Normal Population, could not be transmitted in full and correct form by wire. Please call 317/277-6265 to request an immediate facsimile transmission of the full package insert including this table. The figure following Table 1 entitled Single Dose Average Plasma Concentrations vs. Time in Normal Adult Volunteers, could not be transmitted in full and correct form by wire. Please call 317/277-6265 to request an immediate facsimile transmission of the full package insert including this figure. Effects of Humatrope treatment in adults with somatropin deficiency: Two multicenter trials in adult onset somatropin deficiency (n=98) and two studies in childhood onset somatropin deficiency (n=67) were designed to assess the effects of replacement therapy with Humatrope. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters, and the Nottingham Health Profile. The Nottingham Health Profile is a general health-related quality of life questionnaire. These four studies each included a 6-month randomized, blinded, placebo-controlled phase followed by 12 months of open-label therapy for all patients. The Humatrope dosages for all studies were identical: one month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day. Adult onset patients and childhood onset patients differed by diagnosis (organic versus idiopathic pituitary disease), body size (normal versus small for mean height and weight), and age (mean = 44 versus 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. 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