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| |  Saizen Cleared by FDA for Children with Growth Hormone Deficiency NORWELL, Mass., Oct. 15, 1995 -- Serono Laboratories, Inc., today announced that the U.S. Food and Drug Administration (FDA) authorized Saizen(R) [somatropin (rDNA origin) for injection] for marketing in the United States for the treatment of children with growth failure due to inadequate levels of growth hormone. This is the third favorable FDA decision for Serono, rendered by the Agency within just six weeks, and marks an unprecedented achievement for the company. On August 23, the FDA granted marketing authorization for the company's human growth hormone (rDNA origin), under the tradename Serostim(TM), for the treatment of AIDS wasting or cachexia. Fertinex(TM) (urofollitropin for injection, purified), also received FDA clearance on August 23, which is the first highly purified follicle stimulating hormone (FSH) authorized for marketing in the U.S. Fertinex is indicated for patients undergoing infertility treatments with Assisted Reproductive Technologies, such as in vitro fertilization (IVF), as well as for infertile patients with polycystic ovary disease (PCO). "The significance of having three of our products receive marketing clearance in a six week period is important for our company and our patients," said Ernesto Bertarelli, chief executive officer of Ares-Serono. "This is yet another sign of our commitment to developing our presence in the United States and offering patients and doctors improved quality of care through innovative research and development in four important therapeutic fields, fertility, growth, metabolic disorders and immunology." Saizen [somatropin (rDNA origin) for injection] For subcutaneous or intramuscular injection Description Saizen [somatropin (rDNA origin) for injection] is a human growth hormone produced by recombinant DNA technology. Saizen has 191 amino acid residues and a molecular weight of 22,125 daltons. Its amino acid sequence and structure are identical to the dominant form of human pituitary growth hormone. Saizen is produced by a mammalian cell line (mouse C127) that has been modified by the addition of the human growth hormone gene. Saizen, with the correct three-dimensional configuration, is secreted directly through the cell membrane into the cell-culture medium for collection and purification. Saizen is a highly purified preparation. Biological potency is determined by measuring the increase in body weight induced in hypophysectomized rats. Saizen is a sterile, non-pyrogenic, white, lyophilized powder intended for subcutaneous or intramuscular injection after reconstitution with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol). The reconstituted solution has a pH of 6.5 to 8.5. Saizen is available in vials. The quantitative composition per vial is: 5 mg (approximately 15 IU) vial: Each vial contains 5.0 mg somatropin (approximately 15 IU), 34.2 mg sucrose and 1.165 mg O-phosphoric acid. The pH is adjusted with sodium hydroxide or 0-phosphoric acid. 6 mg (approximately 18 IU) vial: Each vial contains 6.0 mg somatropin (approximately 18 IU), 41.04 mg sucrose and 1.398 mg 0-phosphoric acid. The pH is adjusted with sodium hydroxide or 0-phosphoric acid. The diluent is Bacteriostatic Water for Injection, USP containing 0.9% Benzyl Alcohol added as an antimicrobial preservative. Clinical Pharmacology General In vitro, preclinical, and clinical testing have demonstrated that Saizen [somatropin (rDNA origin) for injection] is therapeutically equivalent to pituitary-derived human growth hormone. Clinical studies in normal adults also demonstrated equivalent pharmacokinetics. Actions that have been demonstrated for Saizen, somatrem, and/or pituitary-derived human growth hormone include: A. Tissue Growth 1. Skeletal Growth: Saizen stimulates skeletal growth in prepubertal children with pituitary growth hormone deficiency. Skeletal growth is accomplished at the epiphyseal plates at the ends of long bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by growth hormone and one of its mediators, insulin-like growth factor-I. Serum levels of insulin-like growth factor-I are low in children and adolescents who are growth hormone deficient, but increase during treatment with Saizen. Linear growth continues until the growth plates fuse at the end of puberty. 2. Cell Growth: Treatment with pituitary-derived human growth hormone results in an increase in both the number and the size of skeletal muscle cells. 3. Organ Growth: Growth hormone of human pituitary origin influences the size and function of internal organs and increases red cell mass. Saizen has been shown to promote similar organ weight increase to pituitary human growth hormone in an adequate animal model. B. Protein Metabolism Linear growth is facilitated in part by growth hormone-stimulated protein synthesis. This is reflected by increased cellular uptake of amino acids and nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during growth hormone therapy. C. Carbohydrate Metabolism Growth hormone is a modulator of carbohydrate metabolism. Children with inadequate secretion of growth hormone sometimes experience fasting hypoglycemia that is improved by treatment with growth hormone. Saizen therapy may decrease glucose tolerance. Administration of Saizen to normal adults and patients with growth hormone deficiency resulted in transient increases in mean serum fasting and postprandial insulin levels. However, glucose levels remained in the normal range. D. Lipid Metabolism Acute administration of human growth hormone to humans results in lipid mobilization. Nonesterified fatty acids increase in plasma within one hour of Saizen administration. In growth hormone deficient patients, long-term growth hormone administration often decreases body fat. Mean cholesterol levels decreased in patients treated with Saizen. The clinical significance of this is unknown. E. Mineral Metabolism Growth hormone administration results in the retention of total body potassium, phosphorus, and sodium. Serum calcium levels appear to be unaffected. F. Connective Tissue/Bone Metabolism Growth hormone stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline. Pharmacokinetics Absorption - The absolute bioavailability of recombinant growth hormone (r-hGH) after subcutaneous administration ranges between 70-90%. Distribution - The mean volume of distribution of r-hGH given to healthy volunteers was estimated to be 12.0 +/- 1.08 L. Metabolism - 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 is returned to the systemic circulation. The mean half-life of intravenous somatropin in normal males is 0.6 hours, whereas subcutaneously and intramuscularly administered somatropin has a half-life of 1.75 and 3.4 hours, respectively. The longer half-life observed after subcutaneous or intramuscular administration is due to slow absorption from the injection site. Excretion - The mean clearance of intravenously administered r-hGH in six normal male volunteers was 14.6 +/- 2.8 L/hr. Special Populations Pediatric - The pharmacokinetics of r-hGH is similar in children and adults. Gender - No gender studies have been performed in children. In adults, the clearance of r-hGH in both men and women tends to be similar. Race - No data are available. Renal Insufficiency - Children and adults with chronic renal failure tend to have decreased clearance of r-GH as compared to normals. Hepatic Insufficiency - A reduction in r-hGH clearance has been noted in patients with hepatic dysfunction as compared with normal controls. Indications and Usage Saizen [somatropin (rDNA origin) for injection] is indicated for the long- term treatment of children with growth failure due to inadequate secretion of endogenous growth hormone. Contraindications In general, Saizen [somatropin (rDNA origin) for injection] is contraindicated in the presence of active neoplasia. Any pre-existing neoplasia should be inactive and its treatment complete prior to instituting therapy with Saizen. Saizen should be discontinued if there is evidence of recurrent activity. Since, in rare instances, growth hormone deficiency may be an early sign of the presence of a brain tumor, the presence of such a tumor should be ruled out prior to initiation of treatment. Available information suggests that the rate of tumor recurrence is not increased by growth hormone therapy. Saizen should not be used for growth promotion in pediatric patients with closed epiphyses. Saizen reconstituted with Bacteriostatic Water for Injection, USP (0.9% Benzyl Alcohol) should not be administered to patients with a known sensitivity to Benzyl Alcohol. (See "WARNINGS"). Warnings Benzyl Alcohol as a preservative in Bacteriostatic Water for Injection, USP has been associated with toxicity in newborns. If sensitivity to the diluent occurs, Saizen [somatropin (rDNA origin) for injection] may be reconstituted with Sterile Water for Injection, USP. When Saizen is reconstituted in this manner, the reconstituted solution should be used immediately and any unused solution should be discarded. Precautions General: Saizen [somatropin (rDNA origin) for injection] therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of growth disorders. Because human growth hormone may induce a state of insulin resistance, patients should be observed for evidence of glucose intolerance. Human growth hormone should be used with caution in patients with diabetes mellitus or a family history of diabetes mellitus. Hypothyroidism may develop during Saizen therapy. Untreated hypothyroidism will jeopardize the response to growth hormone. Therefore, thyroid hormone determinations should be performed periodically during Saizen administration and thyroid hormone replacement should be initiated when indicated. Bone age should be monitored periodically during Saizen administration especially in patients who are pubertal and/or receiving concomitant thyroid replacement therapy. Under these circumstances, epiphyseal maturation may progress rapidly.
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