HUMALOG® Mix 50/50
(50% insulin lispro protamine suspension and 50% insulin lispro injection, [rDNA origin]) Injection
TABLE OF CONTENTS
Humalog® Mix 50/50™ [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 Mix 50/50 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 Mix 50/50 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 Mix 50/50 has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% may have been added to adjust pH.
|2. INDICATIONS AND USAGE|
Humalog Mix 50/50, a mixture of 50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin), is indicated in the treatment of patients with diabetes mellitus the control of hyperglycemia. Based on cross-study comparisons of the pharmacodynamics of Humalog Mix 50/50 and Humulin 50/50, it is likely that Humalog Mix 50/50 has a more rapid onset of glucose-lowering activity compared with Humulin 50/50 while having a similar duration of action. This profile is achieved by combining the rapid onset of Humalog with the intermediate action of insulin lispro protamine suspension.
|3. DOSAGE AND ADMINISTRATION|
Humalog Mix 50/50 is intended only for subcutaneous administration. Humalog Mix 50/50 should not be administered intravenously. Dosage regimens of Humalog Mix 50/50 will vary among patients and should be determined by the healthcare provider familiar with the patient’smetabolic needs, eating habits, and other lifestyle variables. Humalog 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 ofshorter duration. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate of insulin lispro from subcutaneous tissue.
Direct comparison between Humalog Mix 50/50 and Humulin 50/50 was not performed. However, a cross-study comparison suggests that Humalog Mix 50/50 has a duration of activity that is similar to Humulin 50/50.
Humalog Mix 50/50 should be inspected visually before use. Humalog Mix 50/50 should be used only if it appears uniformly cloudy after mixing. Humalog Mix 50/50 should not be usedafter its expiration date.
Humalog Mix 50/50 is contraindicated during episodes of hypoglycemia and in patients hypersensitive to Humalog Mix 50/50 or one of its excipients.
|5. MECHANISM OF ACTION|
The primary activity of insulin, including Humalog Mix 50/50, 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 Mix 50/50, 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.
|6. USE IN SPECIFIC POPULATIONS|
6.1 Usage in Pregnancy
Teratogenic Effects – Pregnancy Category B
There are no adequate and well-controlled studies with Humalog Mix 50/50 in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
6.2 Nursing Mothers
It is unknown whether insulin lispro is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog Mix 50/50 is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog Mix 50/50 dose, meal plan, or both.
6.3 Pediatric Patients
Safety and effectiveness of Humalog Mix 50/50 in children have not been established.
6.4 Geriatric Patients
Clinical studies of Humalog Mix 50/50 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in this population.
|7. WARNINGS AND PRECAUTIONS|
Humalog differs from Regular human insulin by its rapid onset of action as well as a shorter duration of activity. Therefore, the dose of Humalog Mix 50/50 should be given within 15 minutes before a meal.
Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog Mix 50/50. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes.
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g.,, Regular, NPH, analog), species, or method of manufacturer may result in the need for a change in dosage.
Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog Mix 50/50 and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (e.g., patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level).
Fixed ratio insulins are typically dosed on a twice daily basis, i.e., before breakfast and supper, with each dose intended to cover two meals or a meal and snack (see DOSAGE AND ADMINISTRATION). The dose of insulin required to provide adequate glycemic control for one of the meals may result in hyper- or hypoglycemia for the other meal. The pharmacodynamic profile may also be inadequate for patients (e.g. pregnant women) who require more frequent meals.
Adjustments in insulin dose or insulin type may be needed during illness, emotional stress, and other physiologic stress in addition to changes in meals and exercise.
The pharmacokinetic and pharmacodynamic profiles of all insulins may be altered by the site used for injection and the degree of vascularization of the site. Smoking, temperature, and exercise contribute to variations in blood flow and insulin absorption. These and other factors contribute to inter- and intra-patient variability.
Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.
Renal Impairment– As with other insulins, the requirements for Humalog Mix 50/50 may bereduced in patients with renal impairment.
Hepatic Impairment– Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog Mix 50/50, may be necessary.
Allergy– Local Reactions – As with any insulin therapy, patient may experience erythema, swelling, and pruritus at the injection site. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.
Systemic Reactions– Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.
Antibody production– In clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both human insulin mixtures and human lispro mixtures treatment groups.
|8. ADVERSE REACTIONS|
Clinical studies comparing Humalog Mix 50/50 with human insulin mixtures did not demonstrate a difference in frequency of adverse events between the two treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as whole: Allergic reactions (see PRECAUTIONS, Allergy).
Skin and Appendages: Local injection site reactions or rash or pruritus (see PRECAUTIONS, Allergy).
Hypoglycemia: see WARNINGS and PRECAUTIONS.
Excess insulin may cause hypoglycemia and hypokalemia, particularly after IV 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.
|10. DRUG INTERACTIONS|
A number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.
• The following are examples of substances that may reduce insulin requirement: oral hypoglycemic agents (OHA), octreotide, monoamine oxidase inhibitors (MAOI), non-selective beta-blocking agents, angiotensin converting enzyme (ACE) inhibitors, salicylates, alcohol, sulphonamide antibiotics, anabolic steroids, quinine, quinidine and alpha-adrenergic blocking agents.
• The following are examples of substances that may increase insulin requirement: oral contraceptives, thiazides, glucocorticoids, thryroid hormones and sympathomimetics, growth hormone, diazoxide, asparaginase and nicotinic acid.
• Beta-blocking agents may mask the symptoms of hypoglycemia and delay recovery from hypoglycemia.
• Alcohol may intensify and prolong the hypoglycemic effect of insulin.
Studies in nondiabetic subjects and patients with type 1 (insulin-dependent) diabetes demonstrated that Humalog, the rapid-acting component of Humalog Mix 50/50, 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 Mix 50/50 or Humulin 50/50 in Healthy Nondiabetic Subjects.
Humalog Mix 50/50 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 Mix 50/50, 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 Mix 50/50 (see Figure 1).
Direct comparison of Humalog Mix 50/50 and Humulin 50/50 was not performed. However, a cross-study comparison shown in Figure 1 suggests that Humalog Mix 50/50 has a more rapid absorption than Humulin 50/50.
Radiolabeled distribution studies of Humalog Mix 50/50 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.
Human metabolism studies of Humalog Mix 50/50 have not been conducted. Studies in animals indicate that the metabolism of Humalog, the rapid-acting component of Humalog Mix 50/50, is identical to that of Regular human insulin.
Humalog Mix 50/50 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 Mix 50/50 because of the prolonged insulin lispro protamine suspension absorption.
|12. HOW SUPPLIED/STORAGE AND HANDLING|
1) How Available:
a) Brand names: HUMALOG MIX 50/50, by Lilly.
b) Generic drugs: None.
2) How Supplied:
Humalog Mix 50/50 is available in the following package sizes, each contains 100 Units/mL:
Humalog Mix 50/50 should be stored in a refrigerator [2° to 8°C (36° to 46°F)], but not in the freezer. Do not use if it has been frozen.
Unrefrigerated [below 30 oC (86 oF)] Humalog Mix 50/50 vials must be used within 28 days or be discarded, even if they still contain Humalog Mix 50/50.
Unrefrigerated [below 30 oC (86 oF)] Humalog Mix 50/50 Pens, and KwikPens must be used within 10 days or be discarded, even if they still contain Humalog Mix 50/50.
Protect from direct heat and light. See table below: