Insulin lispro, human

Humalog Mix75/25™ [75% insulin lispro protamine suspension and 25% insulin lispro injection, (rDNA origin)] is a mixture of insulin lispro solution, a rapid-acting blood glucose-lowering agent and insulin lispro protamine suspension, an intermediate-acting blood glucose-lowering agent. Chemically, insulin lispro 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. Insulin lispro 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. Insulin lispro protamine suspension (NPL component) is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation.

Insulin lispro has the following primary structure:

Insulin lispro has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808, both identical to that of human insulin.

Humalog Mix75/25 disposable insulin delivery devices contain a sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection.

Each milliliter of Humalog Mix75/25 injection contains insulin lispro 100 Units, 0.28 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 1.76 mg m -cresol, zinc oxide content adjusted to provide 0.025 mg zinc ion, 0.715 mg phenol, and water for injection. Humalog Mix75/25 has a pH of 7.0-7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust pH.

Antidiabetic Activity --The primary activity of insulin, including Humalog Mix75/25, 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.

Insulin lispro, the rapid-acting component of Humalog Mix75/25, has been shown to be equipotent to regular human insulin on a molar basis. One unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin, but its effect is more rapid and of shorter duration. Humalog Mix75/25 has a similar glucose-lowering effect as compared to Humulin 70/30 on a unit for unit basis.

Pharmacokinetics--

Absorption --Studies in nondiabetic subjects and patients with type 1 (insulin-dependent) diabetes demonstrated that Humalog, the rapid-acting component of Humalog Mix75/25, is absorbed faster than regular human insulin (U-100). In nondiabetic subjects given subcutaneous doses of Humalog ranging from 0.1-0.4 U/kg, peak serum concentrations were observed 30-90 minutes after dosing. When nondiabetic subjects received equivalent doses of regular human insulin, peak insulin concentrations occurred 50-120 minutes after dosing. Similar results were found in patients with type 1 diabetes.

Humalog Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged action of insulin lispro protamine suspension. In 30 nondiabetic subjects given subcutaneous doses (0.3 U/kg) of Humalog Mix75/25, peak serum concentrations were observed 30 to 240 minutes (median, 60 minutes) after dosing ( Figure 2 ). Identical results were found in patients with type 1 diabetes. The rapid absorption characteristics of Humalog are maintained with Humalog Mix75/25 ( Figure 2 ).

Figure 2 represents serum insulin concentration versus time curves of Humalog Mix75/25 and Humulin 70/30. Humalog Mix75/25 has a more rapid absorption than Humulin 70/30, which has been confirmed in patients with type 1 diabetes.

Distribution --radiolabeled distribution studies of Humalog Mix75/25 have not been conducted. However, the volumeof distribution following injection of Humalog is identical to that of regular human insulin, with a range of 0.26-0.36 L/kg.

Metabolism --Human metabolism studies of Humalog Mix75/25 have not been conducted. Studies in animals indicate that the metabolism of Humalog, the rapid-acting component of Humalog Mix75/25, is identical to that of regular human insulin.

Elimination --Humalog Mix75/25 has two absorption phases, a rapid and a prolonged phase, representative of the insulin lispro and insulin lispro protamine suspension components of the mixture. As with other intermediate-acting insulins, a meaningful terminal phase half-life cannot be calculated after administration of Humalog Mix75/25 because of the prolonged insulin lispro protamine suspension absorption.

Pharmacodynamics --Studies in nondiabetic subjects 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 regular human insulin. The early onset of activity of Humalog Mix75/25 is directly related to the rapid absorption of Humalog. The time course of action of insulin and insulin analogs such as Humalog (and hence Humalog Mix75/25) may vary considerably in different individuals or within the same individual. The parameters of Humalog Mix75/25 activity (time of onset, peak time, and duration) as presented in Figures 2 , 3 , and 4 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 General under PRECAUTIONS ).

In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose-lowering activity of Humalog, Humalog Mix75/25, Humalog Mix50/50™ and insulin lispro protamine suspension were compared ( Figure 3 ). Graphs of mean glucose infusion rate versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of Humalog was maintained in Humalog Mix75/25.

In separate glucose clamp studies performed in nondiabetic subjects, glucodynamics of Humalog Mix75/25 and Humulin 70/30 were assessed and are presented in Figure 4 . Humalog Mix75/25 has a duration of activity similar to that of Humulin 70/30.

Figures 3 and 4 represent insulin activity profiles as measured by glucose clamp studies in healthy nondiabetic subjects.

Figure 3 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog Mix50/50, and insulin lispro protamine suspension (NPL component).

Figure 4 is a comparison of the time activity profiles of Humalog Mix75/25 ( Figure 4a ) and of Humulin 70/30 ( Figure 4b ) from two different studies.

Special Populations--

Age and Gender --Information on the effect of age on the pharmacokinetics of Humalog Mix75/25 is unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and women administered Humalog Mix75/25 showed no gender differences. In large Humalog clinical trials, subgroup analyses based upon age and gender demonstrated that differences between Humalog and regular human insulin in postprandial glucose parameters are maintained across sub-groups.

Smoking --The effect of smoking on the pharmacokinetics and glucodynamics of Humalog Mix75/25 has not been studied.

Pregnancy --The effect of pregnancy on the pharmacokineticsand glucodynamics of Humalog Mix75/25 has not been studied.

Obesity --The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and glucodynamics of Humalog Mix75/25 has not been studied. In large clinical trials, which included patients with Body-Mass-Index up to and including 35 kg/m 2 , no consistent differences were observed between Humalog and Humulin R with respect to postprandial glucose parameters.

Renal Impairment --The effect of renal impairment on the pharmacokinetics and glucodynamics of Humalog Mix75/25 has not been studied. In a study of 25 patients with type 2 diabetes and a wide range of renal function, the pharmacokinetic differences between Humalog and human regular insulin were generally maintained. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Careful glucose monitoring and dose reductions of insulin, including Humalog Mix75/25, may be necessary in patients with renal dysfunction.

Hepatic Impairment --Some studies with human insulin have shown increased circulating levels of insulin in patients with hepatic failure. The effect of hepatic impairment on the pharmacokinetics and glucodynamics of Humalog Mix75/25 has not been studied. However, in a study of 22 patients with type 2 diabetes, impaired hepatic function did not affect the subcutaneous absorption or general disposition of Humalog when compared to patients with no history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorption and elimination when compared to regular human insulin. Careful glucose monitoring and dose adjustments of insulin, including Humalog Mix75/25, may be necessary in patients with hepatic dysfunction.

Humalog Mix75/25, a mixture of 75% insulin lispro protamine suspension and 25% insulin lispro, is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog Mix75/25 has a more rapid onset of glucose-lowering activity compared to Humulin 70/30 while having a similar duration of action. This profile is achieved by combining the rapid onset of Humalog with the intermediate action of insulin lispro protamine suspension.

Humalog Mix75/25 is contraindicated during episodes of hypoglycemia and in patients sensitive to insulin lispro or any of the excipients contained in the formulation.

Humalog Mix75/25 is intended only for subcutaneous administration. Humalog Mix75/25 should not be administered intravenously. Dosage regimens of Humalog Mix75/25 will vary among patients and should be determined by the health care professional familiar with the patient's metabolic needs, eating habits, and other lifestyle variables. Humalog has been shown to be equipotent to regular human insulin on a molar basis. One unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin, but its effect is more rapid and of shorter duration. Humalog Mix75/25 has a similar glucose-lowering effect as compared to Humulin 70/30 on a unit for unit basis. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate of insulin lispro from subcutaneous tissue.

Humalog Mix75/25 starts lowering blood glucose more quickly than regular human insulin, allowing for convenient dosing immediately before a meal (within 15 minutes). In contrast, mixtures containing regular human insulin should be given 30-60 minutes before a meal.

The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. As with all insulin preparations, the time course of action of Humalog Mix75/25 may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques.

Humalog Mix75/25 should be inspected visually before use. Humalog Mix75/25 should be used only if it appears uniformly cloudy after mixing. Humalog Mix75/25 should not be used after its expiration date.