Because NovoLog® Mix 70/30 has peak pharmacodynamic activity one hour after injection, it should be administered with meals.
NovoLog® Mix 70/30 should not be administered intravenously.
NovoLog® Mix 70/30 is not to be used in insulin infusion pumps.
NovoLog® Mix 70/30 should not be mixed with any other insulin product.
Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® Mix 70/30. 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), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) 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 NovoLog® Mix 70/30 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.
As with all insulin preparations, hypoglycemic reactions may be associated with the administration of NovoLog® Mix 70/30. 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.
Clinical or pharmacology studies with NovoLog® Mix 70/30 in diabetic patients with various degrees of renal impairment have not been conducted. As with other insulins, the requirements for NovoLog® Mix 70/30 may be reduced in patients with renal impairment.
Clinical or pharmacology studies with NovoLog® Mix 70/30 in diabetic patients with various degrees of hepatic impairment have not been conducted. As with other insulins, the requirements for NovoLog® Mix 70/30 may be reduced in patients with hepatic impairment.
Local Reactions- Erythema, swelling, and pruritus at the injection site have been observed with NovoLog® Mix 70/30 as with other 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
Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial. Changes in cross-reactive antibodies were more common after NovoLog® Mix 70/30 than with Novolin® 70/30 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
Patients should be informed about potential risks and advantages of NovoLog® Mix 70/30 therapy including the possible side effects. 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 dose, 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 70/30 during pregnancy or lactation (see PRECAUTIONS, Pregnancy).
The therapeutic response to NovoLog® Mix 70/30 should be assessed by measurement of serum or blood glucose and glycosylated hemoglobin.
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 increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g. octreotide), sulfonamide antibiotics.
The following are examples of substances that may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives).
Beta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin.
Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
In addition, under the influence of sympatholytic medical products such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of hypoglycemia may be reduced or absent (see CLINICAL PHARMACOLOGY).
Mixing of insulins
NovoLog® Mix 70/30 should not be mixed with any other insulin product.
Carcinogenesis, mutagenesis, impairment of fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog® Mix 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog® Mix 70/30, 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
Animal reproduction studies have not been conducted with NovoLog® Mix 70/30. However, reproductive toxicology and teratology studies have been performed with NovoLog® (the rapid-acting component of NovoLog® Mix 70/30) 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.
It is not known whether NovoLog® Mix 70/30 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 70/30 in pregnant women. NovoLog® Mix 70/30 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is unknown whether NovoLog® Mix 70/30 is excreted in human milk as is human insulin. There are no adequate and well-controlled studies of the use of NovoLog® Mix 70/30 or NovoLog® in lactating women.
Safety and effectiveness of NovoLog® Mix 70/30 in children have not been established.
Clinical studies of NovoLog® Mix 70/30 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.