To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: Humalog Now Available for Diabetes URL: http://www.pslgroup.com/dg/9ED6.htm Doctor's Guide August 12, 1996
INDIANAPOLIS, August 12, 1996-- The first new insulin in 14 years is now on pharmacy shelves and ready for consumers to purchase with a doctor's prescription. Eli Lilly and Company announced today that Humalog(R) (insulin lispro injection (rDNA origin)) is being promoted by its sales representatives and is now available in 10 ml vials across the United States. Cartridges of Humalog for use in insulin injection pens are expected to be available soon. The new rapid-acting insulin was cleared for marketing by the U.S. Food and Drug Administration on June 14. Humalog is a new type of insulin that more closely mimics the body's natural insulin response after eating a meal. Humalog offers people with diabetes an additional resource with which to manage their disease -- one that is more flexible and convenient than traditional insulin therapies. People with diabetes live with major inconveniences -- they monitor blood glucose levels daily, take medications or sometimes inject insulin several times a day to help their bodies process food. For people who are using regular human insulin, injections should be timed at least 30 to 60 minutes before a meal to allow the medication to begin working. Humalog may offer people more flexibility. Humalog clinical trial participants injected Humalog up to 15 minutes before a meal instead of injecting regular human insulin between 30 and 60 minutes before. Trial evidence showed that Humalog acted faster than regular human insulin to lower blood glucose levels after a meal. The most common side effect observed in these clinical trials was hypoglycemia for both regular human insulin and Humalog patients. Potential side effects associated with the use of all insulins, including Humalog, include hypoglycemia, hypokalemia, lipodystrophy and hypersensitivity. Because of the difference in action, care should be taken in patients when these conditions may be clinically relevant. Because of its rapid onset of action, Humalog should be given up to 15 minutes before a meal. In addition to its quicker onset of action, Humalog has a shorter duration of glucose-lowering activity as compared to regular human insulin; therefore, patients whose basal insulin levels are inadequate will also require longer acting insulins to give optimal glucose control. Humalog was discovered and developed by Lilly scientists who found that the time action of insulin could be accelerated by changing the order of two amino acids in the human insulin molecule. Humalog's time action profile is designed to mimic the body's natural insulin output in response to eating a meal. Lilly is seeking permission to market Humalog in other countries around the world, including the Asia-Pacific region, Canada, Japan, Latin America and New Zealand. The company already has received approval to market the insulin analog in 15 European Union member countries, Australia, Russia, South Africa, Switzerland, Brazil and the Czech Republic. The product is being sold in Russia, Switzerland, South Africa, Germany, the United Kingdom and Sweden. Lilly was the first company in the world to get permission to market a human insulin analog when Russia's Ministry of Health approved Humalog. Other company firsts include commercializing the first insulin product derived from animal pancreases in 1923, and bringing to market the first human insulin of recombinant DNA origin in 1982. 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. Humalog (insulin lispro injection [rDNA origin], Lilly) For more information, see accompanying package insert. Humalog(R) insulin lispro injection (rDNA origin) Description: Humalog(R) (insulin lispro, rDNA origin) is a human insulin analog that is a rapid-acting, parenteral blood glucose-lowering agent. Chemically, it is Lys(B28), Pro(B29) human insulin analog, created when the amino acids at positions 28 and 29 on the insulin B-chain are reversed. Humalog is synthesized in a special non-pathogenic laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for insulin lispro. Humalog has the following primary structure: Figure 1. (Note: Figure 1 could not be transmitted in full and correct form by wire. Please call (317) 276-3570 to request an immediate facsimile transmission of the full package insert including this table.) Humalog has the empirical formula C257 H383 N65 O77 S6 and a molecular weight of 5808, both identical to that of human insulin. The vials and cartridges contain a sterile solution of Humalog for use as an injection. Humalog injection consists of zinc-insulin lispro crystals dissolved in a clear aqueous fluid. Each milliliter of Humalog injection contains insulin lispro 100 Units, 16 mg glycerin, 1.88 mg dibasic sodium phosphate, 3.15 mg m-cresol, zinc oxide content adjusted to provide 0.0197 mg zinc ion, trace amounts of phenol, and water for injection. Insulin lispro has a pH of 7.0-7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH. Clinical Pharmacology: Antidiabetic Activity -- The primary activity of insulin, including Humalog, is the regulation of glucose metabolism. In addition, all insulins have several anabolic and anti-catabolic actions on many tissues in the body. In muscle and other tissues (except the brain), insulin causes rapid transport of glucose and amino acids intracellularly, promotes anabolism, and inhibits protein catabolism. In the liver, insulin promotes the uptake and storage of glucose in the form of glycogen, inhibits gluconeogenesis, and promotes the conversion of excess glucose into fat. Humalog has been shown to be equipotent to human insulin on a molar basis. One unit of Humalog has the same glucose-lowering effect as one unit of human regular insulin, but its effect is more rapid and of shorter duration. The glucose-lowering activity of Humalog and human regular insulin is comparable when administered to normal volunteers by the intravenous route. Pharmacokinetics: Absorption and Bioavailability -- Humalog is as bioavailable as human regular insulin, with absolute bioavailability ranging between 55%-77% with doses between 0.1-0.2 U/kg, inclusive. Studies in normal volunteers and patients with type I (insulin-dependent) diabetes demonstrated that Humalog is absorbed faster than human regular insulin (U100) (Figure 2). In normal volunteers given subcutaneous doses of Humalog ranging from 0.1-0.4 U/kg, peak serum levels were seen 30-90 minutes after dosing. When normal volunteers received equivalent doses of human regular insulin, peak insulin doses occurred between 50-120 minutes after dosing. Similar results were seen in patients with type I diabetes. The pharmacokinetic profiles of Humalog and human regular insulin are comparable to one another when administered to normal volunteers by the intravenous route. Humalog was absorbed at a consistently faster rate than human regular insulin in healthy male volunteers given 0.2 U/kg human regular insulin or Humalog at abdominal, deltoid, or femoral sites, the three sites often used by patients with diabetes. After abdominal administration of Humalog, serum drug levels are higher and the duration of action is slightly shorter than after deltoid or thigh administration. (see Dosage and Administration section). Humalog has less intra- and inter-patient variability compared to human regular insulin. Figure 2 (Note: Figure 2, entitled Serum Humalog and Insulin Levels After Subcutaneous Injection of Human Regular Insulin or Humalog (0.2 U/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type I Diabetes, could not be transmitted in full and correct form by wire. Please call (317) 276-3570 to request an immediate facsimile transmission of the full package insert including this figure.) Distribution -- The volume of distribution for Humalog is identical to that of human regular insulin, with a range of 0.26-0.36 L/kg. Metabolism -- Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Humalog is identical to that of human regular insulin. Elimination -- When Humalog is given subcutaneously, its t1/2 is shorter than that of human regular insulin (1 vs 1.5 hours, respectively). When given intravenously, Humalog and human regular insulin show identical dose-dependent elimination, with a t1/2 of 26 and 52 minutes at 0.1 U/kg and 0.2 U/kg, respectively. Pharmacodynamics -- Studies in normal volunteers and patients with diabetes demonstrated that Humalog has a more rapid onset of glucose-lowering activity, an earlier peak for glucose lowering, and a shorter duration of glucose-lowering activity than human regular insulin (Figure 3). The earlier onset of activity of Humalog is directly related to its more rapid rate of absorption. The time course of action of insulin and insulin analogs such as Humalog may vary considerably in different individuals or within the same individual. The parameters of Humalog activity (time of onset, peak time, and duration) as designated in Figure 3 should be considered only as general guidelines. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables (see Precautions, Absorption and Bioavailability sub-section). In open-label, crossover studies of 1008 patients with type I diabetes and 722 patients with type II (non-insulin-dependent) diabetes, Humalog reduced postprandial glucose compared with human regular insulin (see Table). The clinical significance of improvement in postprandial hyperglycemia has not been established. In 12-month parallel studies of type I and type II patients, hemoglobin A1c did not differ between patients treated with human regular insulin and those treated with Humalog. While the overall rate of hypoglycemia did not differ between patients with type I and type II diabetes treated with Humalog compared with human regular insulin, patients with type I diabetes treated with Humalog had fewer hypoglycemic episodes between midnight and 6 a.m. The lower rate of hypoglycemia in the Humalog-treated group may have been related to higher nocturnal blood glucose levels, as reflected by a small increase in mean fasting blood glucose levels. Special Populations: Age and Gender -- Information on the effect of age and gender on the pharmacokinetics of Humalog is unavailable. However, in large clinical trials, subgroup analysis based on age and gender did not indicate any difference in postprandial glucose parameters between Humalog and human regular insulin. Figure 3 (Note: Figure 3, entitled Blood glucose levels after subcutaneous injection of human regular insulin or Humalog (0.2 U/kg) immediately before a high carbohydrate meal in 10 patients with Type I diabetes, could not be transmitted in full and correct form by wire. Please call (317) 276-3570 to request an immediate facsimile transmission of the full package insert, including this figure.) Table. (Note: The Table entitled Comparison of Means of Glycemic Parameters at the End of Combined Treatment Periods, could not be transmitted in full and correct form by wire. Please call (317) 276-3570 to request an immediate facsimile transmission of the full package insert including this table.) Smoking -- The effect of smoking on the pharmacokinetics and glucodynamics of Humalog has not been studied. --------------------------------------------------------------------------------------------- Copyright © 1999 P\S\L Consulting Group Inc. All rights reserved. Republication or redistribution of P\S\L content is expressly prohibited without the prior written consent of P\S\L. 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