WARNINGS
This human insulin analog differs from human regular insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control. Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. 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 (animal, human), or method of manufacture (rDNA versus animal-source insulin) may result in the need for a change in dosage.
PRECAUTIONS
General-- 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 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). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.
As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stresses. Hypoglycemia-- As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control.
Renal Impairment-- The requirements for insulin may be reduced in patients with renal impairment.
Hepatic Impairment-- Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose mointoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy-- Local Allergy
--As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. 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 a skin cleansing agent or poor injection technique.
Systemic Allergy
--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. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R (N=2969) and 30 patients receiving Humalog (N=2944) (p=.053). Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient.
Antibody Production
--In large clinical trials, antibodies that cross react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy.
Information for Patients --Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, and periodic assessment for diabetes complications.
Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.
Refer patients to the Information for the Patient circular for information on proper injection technique, timing of Humalog dosing (</= 15 minutes before or immediately after a meal), storing and mixing insulin, and common adverse effects.
Use of the Humalog Pen:
Patients should read the "Information for the Patient" insert and the "Disposable Insulin Delivery Device User Manual" before starting therapy with a Humalog Pen and re-read them each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device (refer to "Disposable Insulin Delivery Device User Manual"), prime the pen, and properly dispose of needles. Patients should be advised not to share their pens with others. Laboratory Tests-- As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of glycosylated hemoglobin is recommended for the monitoring of long-term glycemic control.
Drug Interactions-- (see CLINICAL PHARMACOLOGY) Insulin requirements may be increased by medications with hyperglycemic activity such as corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy.
Insulin requirements may be decreased in the presence of drugs with hypoglycemic activity, such as oral hypoglycemic agents, salicylates, sulfa antibiotics, and certain antidepressants (monoamine oxidase inhibitors), certain angiotensin-converting-enzyme inhibitors, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins-- Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, "On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately." Mixing Humalog with Humulin N or Humulin U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with human regular insulin.
The effects of mixing Humalog with insulins of animal source or insulin preparations produced by other manufacturers have not been studied (see WARNINGS).
If Humalog is mixed with a longer-acting insulin, such as Humulin N or Humulin U, Humalog should be drawn into the syringe first to prevent clouding of the Humalog by the longer-acting insulin. Injection should be made immediately after mixing. Mixtures should not be administered intravenously. Carcinogenesis, Mutagenesis, Impairment of Fertility-- Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Humalog. Humalog was not mutagenic in a battery of in vitro and in vivo genetic toxicity assays (bacterial mutation tests, unscheduled DNA synthesis, mouse lymphoma assay, chromosomal aberration tests, and a micronucleus test). There is no evidence from animal studies of Humalog-induced impairment of fertility.
Pregnancy--Teratogenic Effects--Pregnancy Category B-- Reproduction studies have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies 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.
Published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers-- It is unknown whether Humalog 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 is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use-- In a 9-month, cross-over study of pre-pubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by HbAlc was achieved regardless of treatment group: human regular insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, cross-over study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by HbAlc was achieved regardless of treatment group; human regular insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all three treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf-life may be reduced (see DOSAGE AND ADMINISTRATION).
Geriatric Use-- Of the total number of subjects (n=2,834) in eight clinical studies of Humalog, twelve percent (n=338) were 65 years of age or over. The majority of these were type 2 patients. HbAlc values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed.
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