Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen (Page 4 of 5)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The primary activity of insulin, including Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, is the regulation of glucose metabolism. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

12.2 Pharmacodynamics

In a glucose clamp study performed in 30 healthy subjects, the onset of action and glucose-lowering activity of HUMALOG, HUMALOG® Mix50/50™, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, and insulin lispro protamine suspension (ILPS) were compared (see Figure 1). 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 Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25. The median maximum pharmacologic effect of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 after administration of a 0.3 unit/kg dose to healthy subjects occurred at approximately 2 hours (range: 1-6 hours); glucose lowering activity was detectable for a median of 22 hours (range: 13 to 22 hours), which was the end of the clamp.

In separate glucose clamp studies performed in healthy subjects, pharmacodynamics of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 and HUMULIN® 70/30 were assessed and are presented in Figure 2. Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 has a duration of activity similar to that of HUMULIN 70/30.

Figures 1 and 2 should be considered only as representative examples since the time course of action of insulin and insulin analogs, may vary in different individuals or within the same individual.

Figure 1: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG, HUMALOG Mix50/50, Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, or Insulin Lispro Protamine Suspension (ILPS) in 30 Healthy Subjects.

Figure 1
(click image for full-size original)

Figure 2: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 or HUMULIN 70/30 in Healthy Subjects.

Figure 2
(click image for full-size original)

12.3 Pharmacokinetics

Absorption — Insulin Lispro Protamine and Insulin Lispro Injectable Suspension 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 absorption of insulin lispro protamine suspension.

In 31 healthy subjects given subcutaneous doses (0.3 unit/kg) of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, the median peak serum concentration was 60 minutes (range: 30 minutes to 4 hours) after dosing. Identical results were found in patients with type 1 diabetes. The rapid absorption characteristics of HUMALOG are maintained with Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25. Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 has a more rapid absorption than HUMULIN 70/30, which has been confirmed in patients with type 1 diabetes.

Metabolism — Human metabolism studies of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 have not been conducted. However, studies in animals indicate that the metabolism of HUMALOG, the rapid-acting component of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25, is identical to that of regular human insulin.

Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve.

Specific Populations

The effects of age, race, obesity, pregnancy, smoking, or renal or hepatic impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 have not been studied.

Gender — Pharmacokinetic and pharmacodynamic comparisons between men and women administered Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 showed no gender differences.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed with Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25) at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.

Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays.

Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 100 units per mL (U-100) is 75% insulin lispro protamine and 25% insulin lispro, a white and cloudy suspension available as:

3 mL single-patient-use KwikPen (prefilled) NDC 0002-8233-05

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPens must never be shared between patients, even if the needle is changed. Always use a new needle for each injection to prevent contamination.

The Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen dials in 1 unit increments.

16.2 Storage and Handling

Dispense in the original sealed carton with the enclosed Instructions for Use.

Do not use after the expiration date. Protect from direct heat and light. Do not freeze. See storage table below:

Not In-Use (Unopened)Refrigerated(36° to 46°F [2° to 8°C]) Not In Use (unopened) Room Temperature (Below 86°F [30°C]) In-Use (Opened)Room Temperature, (Below 86°F [30°C])
3 mL single-patient-use KwikPen Until expiration date 10 days 10 days, room temperature.Do not refrigerate.

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