Humulin R (U-500)

Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered by the addition of the gene for human insulin production. Humulin R (U-500) consists of zinc-insulin crystals dissolved in a clear fluid. Humulin R (U-500) is a sterile solution and is for subcutaneous injection. It should not be used intravenously or intramuscularly. The concentration of Humulin R (U-500) is 500 units/mL.

Each milliliter contains 500 units of biosynthetic human insulin, 16 mg glycerin, 2.5 mg m -cresol as a preservative, and zinc-oxide calculated to supplement endogenous zinc to obtain a total zinc content of 0.017 mg/100 units. Sodium hydroxide and/or hydrochloric acid may be added during manufacture to adjust the pH.

Humulin R (U-500) is contraindicated in hypoglycemia.

General --Every patient exhibiting insulin resistance who requires Humulin R (U-500) for control of diabetes should be under close observation until appropriate dosage is established. The response will vary among patients. Some patients can be controlled with a single dose daily; others may require 2 or 3 injections per day. Most patients will show a "tolerance" to insulin, so that minor variations in dosage can occur without the development of untoward symptoms of insulin shock.

Insulin resistance is frequently self-limited; after several weeks or months during which high dosage is required, responsiveness to the pharmacologic effect of insulin may be regained and dosage can be reduced.

Information for Patients --Patients should be instructed regarding their dosage and should be reminded that this formulation requires the administration of a smaller volume of solution than is the case with less concentrated formulations.

Laboratory Tests --Blood and urine glucose, glycohemoglobin, and urine ketones should be monitored frequently.

Drug Interactions --The concurrent use of oral hypoglycemic agents with Humulin R (U-500) is not recommended since there are no data to support such use.

Pregnancy-Teratogenic Effects --No reproduction studies have been conducted in animals, and there are no adequate and well-controlled studies in pregnant women. It would be anticipated that the benefits of this insulin preparation would outweigh any risk to the developing fetus.

Nonteratogenic Effects --Insulin does not cross the placenta as does glucose.

Labor and Delivery --Careful monitoring of the patient is required, since the insulin requirement may decrease following delivery.

Nursing Mothers --It is not known whether insulin is excreted in significant amounts in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humulin R (U-500) insulin injection is administered to a nursing woman.

Pediatric Use --There are no special precautions relating to the use of this insulin formulation in the pediatric age group.

As with other human insulin preparations, hypoglycemic reactions may be associated with the administration of Humulin R (U-500). However, deep secondary hypoglycemic reactions may develop 18 to 24 hours after the original injection of Humulin R (U-500). Consequently, patients should be carefully observed, and prompt treatment of such reactions should be initiated with glucagon injections and/or with glucose by intravenous injection or gavage.

Hypoglycemia

Hypoglycemia is one of the most frequent adverse events experienced by insulin users.

Symptoms of mild to moderate hypoglycemia may occur suddenly and can include:

• sweating
• dizziness
• palpitation
• tremor
• hunger
• restlessness
• tingling in the hands, feet, lips, or tongue
• lightheadedness
• inability to concentrate
• headache
• drowsiness
• sleep disturbances
• anxiety
• blurred vision
• slurred speech
• depressive mood
• irritability
• abnormal behavior
• unsteady movement
• personality changes

Signs of severe hypoglycemia can include:

• disorientation
• unconsciousness
• seizures
• death

Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, medications such as beta-blockers, change in insulin preparations, or intensified control (3 or more insulin injections per day) of diabetes.

A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin.

Without recognition of early warning symptoms, the patient may not be able to take steps to avoid more serious hypoglycemia. Patients who experience hypoglycemia without early warning symptoms should monitor their blood glucose frequently, especially prior to activities such as driving. Mild to moderate hypoglycemia may be treated by eating foods or taking drinks that contain sugar. Patients should always carry a quick source of sugar, such as candy mints or glucose tablets.

Hypoglycemia when using Humulin R (U-500) can be prolonged and severe.

Lipodystrophy

Rarely, administration of insulin subcutaneously can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue).

Allergy to Insulin

Local Allergy --Patients occasionally experience erythema, local edema, and pruritus at the site of injection of insulin. This condition usually is self-limiting. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic Allergy --Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy (anaphylaxis) may be life threatening.