Humulin R U-500 (Page 3 of 5)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7% and has been reported to be as high as 20-25% in women with a HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

8.2 Lactation

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including HUMULIN R U-500, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN R U-500 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMULIN R U-500 and any potential adverse effects on the breastfed child from HUMULIN R U-500 or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of HUMULIN R U-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. Use of HUMULIN R U-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. Standard precautions as applied to use of HUMULIN R U-500 in adults are appropriate for use in pediatric patients.

8.5 Geriatric Use

The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

8.6 Renal Impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.

8.7 Hepatic Impairment

Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

10 OVERDOSAGE

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

11 DESCRIPTION

Insulin human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli and has the empirical formula C257 H383 N65 O77 S6 with a molecular weight of 5.808 kDa.

HUMULIN R U-500 (insulin human) injection is a sterile, aqueous, and colorless solution for subcutaneous use. HUMULIN R U-500 contains 500 units of insulin human in each milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin (16 mg), metacresol (2.5 mg), zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH. The pH is 7.0 to 7.8.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. 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 euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m2), single doses of HUMULIN R U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.

Figure 1 should be considered a representative example since the time course of action of insulin may vary in different individuals or within the same individual. 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 Warnings and Precautions (5.3)].

Figure 1
(click image for full-size original)

Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 in Healthy Obese Subjects

12.3 Pharmacokinetics

Absorption ā€” In a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4 hours (50 unit dose) and 8 hours (100 unit dose) with a range of 0.5-8 hours.

Metabolism ā€” The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin.

Elimination ā€” Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy obese subjects (Nā‰„21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN R U-500.

Figure 2
(click image for full-size original)

Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 Healthy Obese Subjects

13 NONCLINICAL TOXICOLOGY

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