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Humalog Mix50 / 50 (Insulin Lispro Subcutaneous) - Description and Clinical Pharmacology

 
 



HUMALOG® Mix50/50TM
50% INSULIN LISPRO PROTAMINE SUSPENSION AND
50% INSULIN LISPRO INJECTION
(rDNA ORIGIN)
UNITS PER ML (U-100)

DESCRIPTION

Humalog® Mix50/50™ [50% insulin lispro protamine suspension and 50% 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 to produce 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 C257H383N65O77S6 and a molecular weight of 5808, both identical to that of human insulin.

Humalog Mix50/50 vials and Pens contain a sterile suspension of insulin lispro protamine suspension mixed with soluble insulin lispro for use as an injection.

Each milliliter of Humalog Mix50/50 injection contains insulin lispro 100 units, 0.19 mg protamine sulfate, 16 mg glycerin, 3.78 mg dibasic sodium phosphate, 2.20 mg Metacresol, zinc oxide content adjusted to provide 0.0305 mg zinc ion, 0.89 mg phenol, and Water for Injection. Humalog Mix50/50 has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust pH.

CLINICAL PHARMACOLOGY

Antidiabetic Activity

The primary activity of insulin, including Humalog Mix50/50, 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 Mix50/50, 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.

Pharmacokinetics

Absorption

Studies in nondiabetic subjects and patients with type 1 (insulin–dependent) diabetes demonstrated that Humalog, the rapid–acting component of Humalog Mix50/50, is absorbed faster than Regular human insulin (U–100). In nondiabetic subjects given subcutaneous doses of Humalog ranging from 0.1 to 0.4 U/kg, peak serum concentrations were observed 30 to 90 minutes after dosing. When nondiabetic subjects received equivalent doses of Regular human insulin, peak insulin concentrations occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes.

Figure 1: Serum Immunoreactive Insulin (IRI) Concentrations, After Subcutaneous Injection of Humalog Mix50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects.

Figure 1: Serum Immunoreactive Insulin (IRI) Concentrations, After Subcutaneous Injection of Humalog Mix50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects.

Humalog Mix50/50 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 healthy nondiabetic subjects given subcutaneous doses (0.3 U/kg) of Humalog Mix50/50, peak serum concentrations were observed 45 minutes to 13.5 hours (median, 60 minutes) after dosing (see Figure 1). In patients with type 1 diabetes, peak serum concentrations were observed 45 minutes to 120 minutes (median, 60 minutes) after dosing. The rapid absorption characteristics of Humalog are maintained with Humalog Mix50/50 (see Figure 1).

Direct comparison of Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross–study comparison shown in Figure 1 suggests that Humalog Mix50/50 has a more rapid absorption than Humulin 50/50.

Distribution

Radiolabeled distribution studies of Humalog Mix50/50 have not been conducted. However, the volume of distribution following injection of Humalog is identical to that of Regular human insulin, with a range of 0.26 to 0.36 L/kg.

Metabolism

Human metabolism studies of Humalog Mix50/50 have not been conducted. Studies in animals indicate that the metabolism of Humalog, the rapid–acting component of Humalog Mix50/50, is identical to that of Regular human insulin.

Elimination

Humalog Mix50/50 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 Mix50/50 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 Mix50/50 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 Mix50/50), may vary considerably in different individuals or within the same individual. The parameters of Humalog Mix50/50 activity (time of onset, peak time, and duration) as presented in Figures 2 and 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 General under PRECAUTIONS).

In a glucose clamp study performed in 30 nondiabetic subjects, the onset of action and glucose–lowering activity of Humalog, Humalog Mix50/50, Humalog® Mix75/25™, and insulin lispro protamine suspension (NPL component) were compared (see Figure 2). 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 Mix50/50.

Direct comparison between Humalog Mix50/50 and Humulin 50/50 was not performed. However, a cross–study comparison shown on Figure 3 suggests that Humalog Mix50/50 has a duration of activity that is similar to Humulin 50/50.

Figure 2: Glucose Infusion Rates (A Measure of Insulin Activity) After Injection of Humalog, Humalog Mix50/50, Humalog Mix75/25, or Insulin Lispro Protamine Suspension (NPL Component) in 30 Nondiabetic Subjects.

Figure 2: Glucose Infusion Rates (A Measure of Insulin Activity) After Injection of Humalog, Humalog Mix50/50, Humalog Mix75/25, or Insulin Lispro Protamine Suspension (NPL Component) in 30 Nondiabetic Subjects.

Figure 3: Insulin Activity After Subcutaneous Injection of Humalog Mix50/50 and Humulin 50/50 in Nondiabetic Subjects.

Figure 3: Insulin Activity After Subcutaneous Injection of Humalog Mix50/50 and Humulin 50/50 in Nondiabetic Subjects.

Figures 2 and 3 represent insulin activity profiles as measured by glucose clamp studies in healthy nondiabetic subjects.

Figure 2 shows the time activity profiles of Humalog, Humalog Mix75/25, Humalog Mix50/50, and insulin lispro protamine suspension (NPL component).

Figure 3 is a comparison of the time activity profiles of Humalog Mix50/50 (see Figure 3a) and of Humulin 50/50 (see Figure 3b) from two different studies.

Special Populations

Age and Gender

Information on the effect of age on the pharmacokinetics of Humalog Mix50/50 is unavailable. Pharmacokinetic and pharmacodynamic comparisons between men and women administered Humalog Mix50/50 showed no gender differences. In large Humalog clinical trials, sub–group analysis based on 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 pharmacodynamics of Humalog Mix50/50 has not been studied.

Pregnancy

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied.

Obesity

The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of Humalog Mix50/50 has not been studied. In large clinical trials, which included patients with Body Mass Index up to and including 35 kg/m2, 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 pharmacodynamics of Humalog Mix50/50 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 Regular human 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 Mix50/50, 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 pharmacodynamics of Humalog Mix50/50 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 with patients with no history of hepatic dysfunction. In that study, Humalog maintained its more rapid absorption and elimination when compared with Regular human insulin. Careful glucose monitoring and dose adjustments of insulin, including Humalog Mix50/50, may be necessary in patients with hepatic dysfunction.

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