Humulin® R U-100 is a polypeptide hormone structurally identical to human insulin synthesized through rDNA technology in a special non-disease-producing laboratory strain of Escherichia coli bacteria. Humulin R U-100 has the empirical formula C257H383N65O77S6 and a molecular weight of 5808.
Humulin R U-100 is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerin 16 mg/mL and metacresol 2.5 mg/mL, endogenous zinc (approximately 0.015 mg/100 units) and water for injection. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.
Adequate insulin dosage permits patients with diabetes to effectively utilize carbohydrates, proteins and fats. Regardless of dose strength, insulin enables carbohydrate metabolism to occur and thus to prevent the production of ketone bodies by the liver. Some patients develop severe insulin resistance such that daily doses of several hundred units of insulin or more are required.
Regulation of glucose metabolism is the primary activity of insulin. Insulin lowers blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis, proteolysis, and gluconeogenesis, and enhance protein synthesis and conversion of excess glucose into fat.
Administered insulin, including Humulin R U-100, substitutes for inadequate endogenous insulin secretion and partially corrects the disordered metabolism and inappropriate hyperglycemia of diabetes mellitus, which are caused by either a deficiency or a reduction in the biologic effectiveness of insulin. When administered in appropriate doses at prescribed intervals to patients with diabetes mellitus, Humulin R U-100 restores their ability to metabolize carbohydrates, proteins and fats.
As with all insulin preparations, the duration of action of Humulin R U-100 is dependent on dose, site of injection, blood supply, temperature, and physical activity.
Humulin R U-100 is human insulin with a short duration of action. With subcutaneous use, the pharmacologic effect of Humulin R U-100 begins approximately 30 minutes (range: 10 to 75 minutes) after administration of doses in the 0.05 to 0.4 units/kg range. The effect is maximal at approximately 3 hours (range: 20 minutes to 7 hours) and terminates after approximately 8 hours (range: 3 to 14 hours). With intravenous use, the pharmacologic effect of Humulin R U-100 begins at approximately 10 to 15 minutes and terminates at a median time of approximately 4 hours (range: 2 to 6 hours) after administration of doses in the range of 0.1 to 0.2 units/kg. The time course of action of any insulin may vary considerably in different individuals or at different times in the same individual.
Subcutaneous use of Humulin R U-100
A 48-month multicenter, open-label, single-arm study was conducted in insulin-naive patients with type 1 or type 2 diabetes (N=129) to assess the safety and efficacy of Humulin R U-100. Humulin R U-100 and Humulin® N (alone or in combination) were administered by subcutaneous injection. Eighty-four percent of patients were Caucasian. Fifty-seven percent of the patients were male. The mean age was 45 years (range: 4 to 83 years). The average weight was 72 kg.
Total mean (± SD) glycohemoglobin improved from baseline to endpoint (baseline: 14.3 ± 3.1%, endpoint: 10.1 ± 2.8%). Hemoglobin A1c was not measured in this study. At baseline, patients weighed 72 ± 23 kg; at endpoint mean weight was 80 ± 22 kg. At endpoint, mean (± SD) total daily insulin doses for Humulin R U-100 were 0.18 ± 0.17 units/kg. At 48 months, 16 patients (21%) reported hypoglycemia. During the study, 4 patients experienced diabetic ketoacidosis.
Intravenous use of Humulin R U-100
The intravenous administration of Humulin R U-100 was tested in 21 patients with type 1 diabetes. The patients’ usual doses of insulin were temporarily held, and blood glucose concentrations were maintained at a range of 200 – 260 mg/dL for one to three hours during a run-in phase of intravenous Humulin R U-100 followed by a 6-hour assessment phase. During the assessment phase patients received intravenous Humulin R at an initial dose of 0.5 U/h, adjusted to maintain blood glucose concentrations near normoglycemia (100 to 160 mg/dL).
The mean blood glucose levels during the assessment phase for patients on Humulin R U-100 therapy are summarized below in Table 1. All patients achieved near normoglycemia during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 20 of 21 patients treated with Humulin R U-100. The average time (± SE) required to attain near normoglycemia was 161 ± 14 minutes for Humulin R U-100.
Excess insulin may cause hypoglycemia and hypokalemia, particularly after intravenous administration. Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. 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 intramuscular/subcutaneous glucagon 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.
DOSAGE AND ADMINISTRATION
Humulin R U-100, when used subcutaneously, is usually given three or more times daily before meals. The dosage and timing of Humulin R U-100 should be individualized and determined, based on the physician’s advice, in accordance with the needs of the patient. Humulin R U-100 may also be used in combination with oral antihyperglycemic agents or longer-acting insulin products to suit the needs of the individual patients with diabetes. The injection of Humulin R U-100 should be followed by a meal within approximately 30 minutes of administration.
The average range of total daily insulin requirement for maintenance therapy in insulin-treated patients without severe insulin resistance lies between 0.5 and 1 unit/kg/day. However, in pre-pubertal children it usually varies from 0.7 to 1 unit/kg/day, but can be much lower during the period of partial remission. In situations of insulin resistance, e.g. during puberty or due to obesity, the daily insulin requirement may be substantially higher. Initial dosages for patients with diabetes are often lower, e.g., 0.2 to 0.4 units/kg/day.
Humulin R U-100 may be administered by subcutaneous injection in the abdominal wall, the thigh, the gluteal region or in the upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region. As with all insulin, the duration of action will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.
Intravenous administration of Humulin R U-100 is possible under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia.
For intravenous use, Humulin R U-100 should be used at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems with the infusion fluids 0.9% sodium chloride using polyvinyl chloride infusion bags.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Never use Humulin R U-100 if it has become viscous (thickened) or cloudy; use it only if it is clear and colorless. Humulin R U-100 should not be used after the printed expiration date.
Mixing of Insulins
- Humulin R U-100 should only be mixed as directed by the physician.
- Humulin R U-100 is short-acting and is often used in combination with intermediate- or long-acting insulins.
- The order of mixing and brand or model of syringe should be specified by the physician. A U-100 insulin syringe should always be used. Failure to use the correct syringe can lead to dosage errors.
- In general, when an intermediate-acting insulin (e.g., NPH insulin isophane suspension) is mixed with short-acting soluble insulin (e.g., regular), the short-acting insulin should be drawn into the syringe first.