NovoLog Mix 50/50 Warnings & Precautions

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NovoLog Mix 50/50 Warnings & Precautions
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WARNINGS

Because NovoLog® Mix 50/50 has peak pharmacodynamic activity between 1 and 4 hours after injection, it should be administered with meals.

NovoLog® Mix 50/50 should not be administered intravenously. NovoLog® Mix 50/50 is not to be used in insulin infusion pumps.NovoLog® Mix 50/50 should not be mixed with any other insulin product.

Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® 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 dose should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (e.g., regular, NPH, analog, premixed), 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 NovoLog® 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). Because there is diurnal variation in insulin resistance and endogenous insulin secretion, variability in the time and content of meals, and variability in the time and extent of exercise, fixed ratio insulin mixtures may not provide optimal glycemic control for all patients. 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.

Insulin may cause sodium retention and edema (swelling of hands and feet), particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy at the injection site and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.

Hypoglycemia - As with all insulin preparations, hypoglycemic reactions may be associated with the administration of NovoLog® Mix 50/50. Rapid changes in serum glucose concentrations 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 - Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients with diabetes with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with renal impairment.

Hepatic Impairment - Clinical or pharmacology studies with NovoLog® Mix 50/50 in patients with diabetes with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for NovoLog® Mix 50/50 may be reduced in patients with hepatic impairment.

Allergy- Local reactions: Erythema, swelling, and pruritus at the injection site have been observed with insulin therapy. Reactions may be related to the insulin molecule, other components in the insulin preparation including protamine and cresol, components in skin cleansing agents, or injection techniques.

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 - Antibodies have not been extensively investigated during the clinical development of NovoLog® Mix 50/50. Antibodies specific to NovoLog® and cross-reactive with both NovoLog® and human insulin have been evaluated previously in connection with the clinical development of NovoLog®. In addition, specific anti-insulin antibodies as well as crossreacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial between NovoLog® Mix 70/30 and human pre-mixed insulin and NovoLog® as well as in a long-term extension trial. Changes in cross-reactive antibodies were more common after NovoLog® Mix 70/30 than with human pre-mixed insulin but these changes did not correlate with change in HbA1c or increase in insulin dose. The clinical significance of these antibodies has not been established. Antibodies did not increase further after long-term exposure (>6 months) to NovoLog® Mix 70/30.

Information for patients - Maintenance of normal or near-normal glucose control is a treatment goal in diabetes mellitus and has been associated with a reduction in diabetes complications. Patients should consult with their healthcare provider before using NovoLog® Mix 50/50 as a mealtime insulin; the decision should be based on the patient's insulin needs for that particular meal. Patients should be informed that alcohol, including beer and wine, may affect their blood sugar when taking NovoLog® Mix 50/50. Patients should be informed about potential risks and advantages of NovoLog® Mix 50/50 therapy including the possible side effects. Patients should be informed that hypoglycemia may impair the ability to concentrate and react, which may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.

Patients should also be offered continued education and advice on insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dosage, instruction for use of injection devices and proper storage of insulin.

Female patients should be advised to discuss with their physician if they intend to, or if they become, pregnant because information is not available on the use of NovoLog® Mix 50/50 during pregnancy or lactation (see PRECAUTIONS, Pregnancy).

Laboratory Tests - The therapeutic response to NovoLog® Mix 50/50 should be assessed by measurement of serum or blood glucose and glycosylated hemoglobin.
Carcinogenicity, Mutagenicity, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog® Mix 50/50. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog® Mix 50/50, at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At a dose of 200 U/kg/day, NovoLog® increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for NovoLog® was not significantly different than for regular human insulin. The relevance of these findings to humans is not known. NovoLog® was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes. In fertility studies in male and female rats, NovoLog® at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.
Pregnancy: Teratogenic Effects: Pregnancy Category C

All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Insulin mixtures, including NovoLog Mix 50/50, may be limited in their ability to provide near-normal glycemic control, as recommended during pregnancy. Careful monitoring of glucose control is essential in patients with diabetes during pregnancy.

It is not known whether NovoLog® Mix 50/50 can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. There are no adequate and well-controlled studies of the use of NovoLog® Mix 50/50 in pregnant women.

Animal reproduction studies have not been conducted with NovoLog® Mix 50/50. However, reproductive toxicology and teratology studies have been performed with NovoLog® (the rapid-acting component of NovoLog® Mix 50/50) and regular human insulin in rats and rabbits. In these studies, NovoLog® was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog® did not differ from those observed with subcutaneous regular human insulin. NovoLog®, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32-times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area), and in rabbits at a dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at a dose of 50 U/kg/day and rabbits at a dose of 3 U/kg/day.

These doses are approximately 8 times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits based on U/body surface area.

Nursing mothers - It is unknown whether NovoLog® Mix 50/50 is excreted in human milk as is human insulin. There are no adequate and well-controlled studies of the use of NovoLog® Mix 50/50 or NovoLog® in lactating women.

Pediatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in children have not been established.

Geriatric Use - Safety and effectiveness of NovoLog® Mix 50/50 in geriatric population have not been studied. 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.

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