Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of action The primary activity of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is the regulation of glucose metabolism. Insulin products including the insulin in NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , exert their specific action through binding to insulin receptors. Insulin binding activates mechanisms to lower blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat while simultaneously inhibiting the output of glucose from the liver. In standard biological assays in mice and rabbits, one unit of NovoLog® (insulin aspart) has the same glucose-lowering effect as one unit of regular human insulin. Pharmacokinetics Bioavailability and Absorption The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NovoLog®) reduces the molecule's rm hexamers as observed with regular human insulin. This results in more rapid absorption from the subcutaneous spaces than seen with regular human insulin. The rapid absorption characteristics of NovoLog® are maintained by NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , containing 50% insulin aspart in soluble form. The remaining 50% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection. In an euglycemic clamp study in patients with type 1 diabetes (n=32) after dosing with 0.4 U/kg of NovoLog® Mix 70/30, 50/50, and NovoLog® on three different study days, a Cmax of 98 mU/L was reached after approximately 80 minutes for NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) (See Table 1). There was diminishing distinction in pharmacokinetics between the two NovoLog Mix formulations at later time points (See Figure 2). Table 1: Pharmacokinetic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix 70/30 and NovoLog® in patients with Type 1 diabetes mellitus NovoLog® Mix 50/50 versus NovoLog® Mix 70/30 NovoLog® versus NovoLog® Mix 50/50 Cmax 1.49 [1.34; 1.65] 2.04 [1.84; 2.26] AUC0-2h 1.48 [1.35; 1.64] 2.01 [1.82; 2.22] Values are expressed as mean ratios [95% confidence intervals] Figure 2. Pharmacokinetic profiles of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 70/30, and NovoLog® in Patients with Type 1 diabetes mellitus The bioavailability of insulin aspart is decreased with increasing protamine sulfate concentration in any NovoLog® Mix formulation. Consequently, exposure of a subcutaneous dose of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) may be reduced in comparison to the comparable dose of insulin aspart (NovoLog® ) and an intermediate insulin that are mixed by the patient prior to injection. No clinical studies have been conducted comparing NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) to proportionate doses of insulin aspart (NovoLog® ) and an intermediate-acting insulin that are mixed by the patient prior to injection. Switching to a regimen that contains a NovoLog® Mix formulation will require careful blood glucose monitoring to ensure adequacy of glycemic control and to avoid hypoglycemia. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables (see PRECAUTIONS, General). The influence of different injection sites on the absorption of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been investigated. Distribution and Elimination NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is a biphasic insulin which contains 50% soluble insulin aspart. NovoLog® has a low binding to plasma proteins, 0 - 9%, similar to regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog® was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin. Pharmacodynamics In an euglycemic clamp study in subjects with type 1 diabetes, a maximum glucose infusion rate (GIRmax) of 6.0 ± 1.7 ter approximately 2.5 hours for NovoLog® Mixmg/kg/min was 50/50 (See Table 2). There was diminishing distinction in pharmacodynamics between the two NovoLog Mix formulations at later time points (See Figure 3). Table 2: Pharmacodynamic Parameters comparing NovoLog® Mix 50/50 to NovoLog® Mix 70/30 and NovoLog®in patients with Type 1 diabetes mellitus NovoLog® Mix 50/50 versus NovoLog® Mix 70/30 NovoLog® versus NovoLog® Mix 50/50 GIRmax 1.29 [1.17; 1.43] 1.49 [1.35; 1.65] AUCGIR,0-2h 1.52 [1.31; 1.78] 1.44 [1.23; 1.67] Values are expressed as mean ratios [95% confidence intervals] Figure 3. Pharmacodynamic profiles of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 70/30, and NovoLog® in patients with Type 1 diabetes mellitus Special populations Children and adolescents - The pharmacokinetic and pharmacodynamic properties of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) have not been assessed in children and adolescents less than 18 years of age. Geriatrics - The effect of age on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied. Gender - The effect of gender on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied. Obesity - The effect of obesity and/or subcutaneous fat thickness on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component (NovoLog®) show no significant effect. Ethnic origin - The effect of ethnic origin on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied Renal impairment - The effect of renal function on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component (NovoLog®) show no significant effect. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including NovoLog® Mix 50/50 may be necessary in patients with renal dysfunction (see PRECAUTIONS, Renal Impairment). Hepatic impairment - The effect of hepatic impairment on the pharmacokinetics and pharmaco­dynamics of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has not been studied but data on the rapid-acting component(NovoLog®) show no significant effect. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including NovoLog® Mix 50/50, may be necessary in patients with he­patic dysfunction (see PRECAUTIONS, Hepatic Impairment). Pregnancy - The effect of pregnancy on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 has not been studied (see PRECAUTIONS, Pregnancy). Smoking- The effect of smoking on the pharmacokinetics and pharmacodynamics of NovoLog® Mix 50/50 has not been studied.

NovoLog® Mix 50/50 50% insulin aspart protamine suspension and 50% insulin aspart injection, (rDNA origin) DESCRIPTION NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) (50% insulin aspart protamine suspension and 50% insulin aspart injection, [rDNA origin]) is an insulin analog suspension containing 50% insulin aspart protamine crystals and 50% soluble insulin aspart. NovoLog® Mix 50/50 is a blood glucose-lowering agent with a rapid onset and an intermediate duration of action. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker's yeast) as the on organism. Insulin aspart (NovoLog® ) has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da. Structural formula: NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is a uniform, white, sterile suspension that contains insulin aspart (B28 asp regular human insulin analog) 100 Units/ml, 16 mg glycerol, 1.50 mg phenol, 1.72 mg metacre­sol, 19.6 μg zinc, 1.25 mg disodium hydrogen phosphate dihydrate, 1.17 mg sodium chloride, and 0.23 mg protamine sulfate. NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has a pH of 7.10 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

INDICATIONS NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is indicated as an adjunct to diet and exercise to improve glycemic control in patients with diabetes mellitus. DOSAGE AND ADMINISTRATION The written prescription for NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should include the full name, to avoid confusion with NovoLog® (insulin aspart) and NovoLog® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection, (rDNA origin). NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should be administered within 15 minutes of meal initiation up to three times daily. It is intended only for subcutaneous injection into the abdominal wall, thigh, or upper arm. NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should not be administered intravenously. No clinical studies have been conducted comparing NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) to proportionate doses of insulin aspart (NovoLog®) and an intermediate-acting insulin that are mixed by the patient prior to injection. Initiating or switching to a regimen that contains a NovoLog® Mix formulation, as with any change in an insulin regimen, will require careful blood glucose monitoring to ensure adequacy of glycemic control and to avoid hypoglycemia. Dose regimens of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) will vary among patients and should be determined by the health care professional familiar with the patient's lifestyle variables. As with all insulins, the duration of action may vary according to the dose, injection site, blood flow, temperature, and level of physical activity and conditioning. Administration using PenFill® Cartridges for 3 mL PenFill® cartridge compatible delivery devices and NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen ® Prefilled syringes PenFill®Cartridges for 3 mL PenFill® cartridge compatible delivery devices* NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) PenFill® suspension should be visually inspected and resuspended immediately before use. The resuspended NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) must appear uniformly white and cloudy. Before inserting the cartridge into the insulin delivery system, roll the cartridge between your palms 10 times. The cartridge should be kept horizontal while rolling. Thereafter, turn the cartridge upside down so that the glass ball moves from one end of the cartridge to the other. Do this at least 10 times. The rolling and turning procedure must be repeated until the suspension appears uniformly white and cloudy. Mixing is easier when the insulin has reached room temperature. Inject immediately. Before each subsequent injection, turn the 3 mL PenFill® cartridge compatible delivery devices* upside down so that the glass ball moves from one end of the cartridge to the other. Repeat this at least 10 times until the suspension appears uniformly white and cloudy. Inject immediately. Always remove the needle after each injection and store the 3 mL PenFill® cartridge compatible delivery device without a needle attached. This prevents contamination and/or infection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination. Used needles or lancets should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly. *NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) PenFill® cartridges are designed for use with Novo Nordisk 3 mL PenFill® cartridge compatible insulin delivery devices, with or without the addition of a NovoPen® 3 PenMate®, and NovoFine® disposable needles. Disposable NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen®Prefilled Syringes NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) suspension should be visually inspected and resuspended immediately before use. The resuspended NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) must appear uniformly white and cloudy. Before use, roll the disposable NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe between your palms 10 times. This procedure should be carried out with the NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe in a horizontal position. Thereafter, turn the disposable NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe upside down so that the glass ball moves from one end of the reservoir to the other. Do this at least 10 times. The rolling and turning procedure must be repeated until the suspension appears uniformly white and cloudy. Mixing is easier when the insulin has reached room temperature. Inject immediately. Before each subsequent injection, turn the disposable NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe upside down so that the glass ball moves from one end of the reservoir to the other at least 10 times and until the suspension appears uniformly white and cloudy. Inject immediately. Always remove the needle after each injection and store the NovoLog®Mix 50/50 FlexPen® Prefilled Syringe without a needle attached. This prevents contamination and/or infection, entry of air into the insulin reservoir, or leakage of insulin and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination. Used needles, or lancets should be placed in sharps containers (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly. HOW SUPPLIED NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is available in the following package sizes: each presentation containing 100 Units of insulin aspart per mL (U-100). 3 mL PenFill® cartridges* NDC xxxx-xxxx-xx 3 mL NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled Syringe NDC xxxx-xxxx-xx * NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) PenFill® cartridges are designed for use with Novo Nordisk 3 mL PenFill® cartridge compatible insulin delivery devices, with or without the addition of a NovoPen® 3 PenMate®, and NovoFine® disposable needles. Recommended Storage Unused NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should be stored in a refrigerator between 2o and 8oC (36o to 46oF). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze or use NovoLog®Mix 50/50 if it has been frozen. PenFill® cartridges or NovoLog®Mix 50/50 FlexPen®Prefilled syringes: Once a cartridge or a NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe is punctured, it may be used for up to 14 days if it is kept at room temperature below 30°C (86°F). Cartridges or NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringes in use should not be stored in the refrigerator. Keep all PenFill® cartridges and NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringes away from direct heat and light. Unpunctured PenFill® cartridges and NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringes can be used until the expiration date printed on the label if they are stored in a refrigerator. After removing NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) PenFill® cartridges or NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringes from the refrigerator it is recommended to let the PenFill® cartridges or NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringe reach room temperature before resuspending the insulin as recommended for first time use. Keep unused PenFill® cartridges and NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) FlexPen® Prefilled syringes in the carton so they will stay clean and protected from light. These storage conditions are summarized in the following table: Not in-use (unopened) Room Temperature (below 30°C [86°F]) Not in-use (unopened) Refrigerated (2°-8°C [36° to 46°F]) In-use (opened) Room Temperature (at or below 30°C [86°F]) 3 mL PenFill® cartridges 14 days Until expiration date 14 days (Do not refrigerate) 3 mL NovoLog® Mix 50/50 FlexPen® 14 days Until expiration date 14 days (Do not refrigerate) Manufactured by: Novo Nordisk A/S, 2880 Bagsvaerd, Denmark. Manufactured for: Novo Nordisk Inc., Princeton, NJ 08540, www.novonordisk-us.com. FDA rev date: 8/26/2008

OVERDOSE 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. CONTRAINDICATIONS NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) is contraindicated during episodes of hypoglycemia and in patients hypersensitive to NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) or any of the excipients.

SIDE EFFECTS During clinical trials the overall adverse event profile of NovoLog® Mix 50/50 was comparable to Novolin® 70/30. Adverse events commonly associated with human insulin therapy include the following: Body as whole: allergic reactions (see PRECAUTIONS, Allergy). Skin and Appendages: Injection site reaction, lipodystrophy, pruritus, rash (see PRECAUTIONS, Allergy). Hypoglycemia: see WARNINGS and PRECAUTIONS. 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 increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, 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 blood­glucose-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 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should not be mixed with any other insulin product.

WARNINGS Because NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) has peak pharmacodynamic activity between 1 and 4 hours after injection, it should be administered with meals. NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should not be administered intravenously. NovoLog® Mix 50/50 is not to be used in insulin infusion pumps.NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) should not be mixed with any other insulin product. Hypoglycemia is the most common adverse effect of insulin therapy, including NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . Patients should be informed about potential risks and advantages of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog®, the rapid-acting component of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) , 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) in pregnant women. Animal reproduction studies have not been conducted with NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) . However, reproductive toxicology and teratology studies have been performed with NovoLog® (the rapid-acting component of NovoLog® Mix 50/50 (50% insulin aspart protamine suspension and 50% insulin aspart injection) ) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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 (50% insulin aspart protamine suspension and 50% insulin aspart injection) 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.