ATC Class:A10AB01

VA Class:HS501

AHFS Class:

• Rapid-acting Insulins 68:20.08.04

Generic Name(s):

• Insulin Aspart

Chemical Name:

• 28^B-Aspartic acid-insulin (human)

Molecular Formula:

• C₂₅₆H₃₈₁N₆₅O₇₉S₆

Insulin aspart (rDNA origin) is a biosynthetic, rapid-acting human insulin analog that is prepared using recombinant DNA technology and genetically modified Saccharomyces cerevisiae .1,2,3,15

Diabetes Mellitus

Insulin aspart is used to control hyperglycemia in the management of diabetes mellitus.1 When administered subcutaneously, insulin aspart has a more rapid onset and shorter duration of action compared with insulin human (regular); therefore, insulin aspart is associated with greater relative reductions in postprandial blood glucose concentrations and may provide greater patient convenience in terms of the timing of insulin injections in relation to meals in patients with type 1 (insulin-dependent) and type 2 (noninsulin-dependent) diabetes mellitus.1,2,3,4,5,10,11 Because of its short onset and duration of action, insulin aspart usually is used in regimens that include an intermediate-acting (e.g., isophane [NPH] insulin) or long-acting insulin.1,15,18,19

Safety and efficacy of insulin aspart administered immediately before meals has been demonstrated by comparison with insulin human (regular) administered 30 minutes before meals in open, clinical studies of 6 months' duration in adults with type 1 or type 2 diabetes mellitus; patients in these studies also received NPH insulin as the basal insulin supplement.1,3,11,12 Glycemic control (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]) was comparable or slightly improved in patients receiving insulin aspart compared with those receiving insulin human.1,3,11,12 Patients receiving insulin aspart required slightly higher total daily dosages of insulin (1-3 units daily), principally due to altered basal insulin requirements.1

Insulin aspart also is administered by continuous subcutaneous infusion using an external controlled-infusion pump (e.g., Minimed^® model 500 series, Disetronic H-TRON series or other equivalent pumps) in patients with type 1 or type 2 diabetes mellitus.1,17 Available data in patients with type 1 diabetes mellitus suggest that continuous subcutaneous administration of insulin aspart provides glycemic control (as measured by glycosylated hemoglobin) that is similar to that provided by continuous subcutaneous administration of buffered human insulin or insulin lispro† therapy.17 In an open-label, short-term trial (16 weeks) in patients with type 2 diabetes mellitus, glycemic control was similar during therapy with insulin aspart administered via an external subcutaneous continuous infusion pump or with preprandial injections of insulin aspart in conjunction with basal isophane insulin injections. These data indicate a similar incidence of hypoglycemia among patients receiving any type of study insulin via external infusion pumps versus a regimen of multiple daily injections.

Insulin aspart has been administered as an IV infusion in a limited number of patients with diabetes mellitus,1 but The American Diabetes Association (ADA) states that insulin aspart offers no advantage over regular crystalline insulin in patients who require IV insulin.

For additional information on the management of diabetes mellitus, see Uses in the Insulins General Statement 68:20.08.

General

Dosage of insulin aspart alone (Novolog^®) or in fixed combination with insulin aspart protamine (Novolog^® Mix 70/30) must be individualized and should be regularly adjusted based on the results of blood glucose determinations.1,6,15,16,18 Whenever possible, patients should self-monitor blood glucose concentrations.6 Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.1 Patients previously receiving insulin may require a change in dosage if insulin therapy is changed to insulin aspart.1

Administration

Insulin aspart alone or in fixed combination with insulin aspart protamine is administered by subcutaneous injection using a conventional insulin syringe, an insulin injection pen (e.g., NovoPen^® 3 PenMate, Novolog^® FlexPen^®), or a compatible insulin delivery device (Innovo^®, InDuo^®).1,10,15,26,28 The manufacturer states that NovoLog^® or Novolog Mix 70/30 PenFill^® cartridges are intended for use with NovoPen^® 3 PenMate^® or a compatible insulin delivery device (Innovo^®, InDuo^®).1,15,26,28

Insulin aspart also is administered by continuous subcutaneous infusion using an external controlled-infusion device (e.g., Minimed^® model 500 series, Disetronic H-TRON series or other equivalent pump).1,13 Insulin aspart is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump.1 Insulin aspart in fixed combination with insulin aspart protamine should not be used in insulin infusion pumps.15 For information on the stability of insulin aspart in external infusion pumps, see Insulin Aspart and Insulin Lispro under Chemistry and Stability: Stability, in the Insulins General Statement 68:20.08.

Because of its short duration of action, insulin aspart is used concomitantly with a longer-acting insulin (e.g., isophane [NPH] insulin human, insulin aspart protamine) to meet basal insulin needs in patients with diabetes mellitus and to provide more optimal glycemic control.1,15 Insulin aspart may be mixed with isophane insulin human.1 Although some attenuation of peak serum insulin aspart concentrations was observed when administered concomitantly with isophane insulin human in the same syringe, the time to peak concentration and total bioavailability of insulin aspart were not substantially affected.1 Whenever insulin aspart is mixed with isophane insulin human, insulin aspart should be drawn into the syringe first in order to avoid transfer of isophane insulin human into the insulin vial.1,10 The mixture should be administered immediately after mixing, and such mixtures should not be administered IV.1 The manufacturer states that the effect of mixing insulin aspart with insulins of animal origin, insulins produced by other manufacturers, or crystalline insulin zinc formulations has not been studied.1

The manufacturer states that insulin aspart in fixed combination with insulin aspart protamine suspension (Novolog^® Mix 70/30) is intended only for subcutaneous administration and should not be given IV.15 To resuspend the mixture in a vial immediately before use, the vial should be rolled gently between the hands 10 times until the suspension appears to be uniformly white and cloudy.15

Before inserting the Novolog^® PenFill^® cartridge into a compatible delivery device, the cartridge should be rolled between the palms 10 times.15 The cartridge should then be turned upside down so that the glass ball inside the cartridge moves the length of the cartridge.15 This rolling and turning of the cartridge should be repeated at least 10 times or until the suspension appears to be uniformly white and cloudy.15 The dose should be injected immediately after resuspension, and the rolling and turning of the cartridge should be repeated before each subsequent injection.15

Similarly, if using the Novolog^® FlexPen^®, the pen should be rolled between the palms 10 times.15 The injection pen should then be turned upside down so that the glass ball inside the pen moves from one end of the reservoir to the other.15 This rolling and turning procedure should be repeated at least 10 times or until the suspension appears uniformly white and cloudy.15 The dose should be injected immediately after resuspension, and the rolling and turning of the FlexPen^® should be repeated before each subsequent injection.15

Insulin aspart is administered immediately (within 5-10 minutes) before a meal.1 Insulin aspart in fixed combination with insulin aspart protamine (Novolog^® Mix 70/30) generally is administered twice daily, 15 minutes before the morning and evening meals, with each dose intended to optimize glycemic control during 2 meals or a meal and a snack.15,18 Insulin aspart can be administered by subcutaneous injection into the abdominal wall, thigh, or upper arm.1 A planned rotation of injection sites within an area should be followed.1,6

Insulin aspart may be administered by IV infusion under proper medical supervision in a clinical setting.1 For IV infusion in polypropylene infusion bags, insulin aspart is usually diluted to a concentration of 0.05-1 units/mL in 0.9% sodium chloride, 5% dextrose, or 10% dextrose injection with 40 mEq/L of potassium chloride.1

Dispensing and Administration Precautions

Because of the similarity in names and product packaging between Novolog^® (insulin aspart) and Novolog^® Mix 70/30 (insulin aspart 30 units/mL with insulin aspart protamine 70 units/mL), the manufacturer has recently implemented color-branded labeling to help prevent dispensing errors.21,23 The current packaging for NovoLog^® Mix 70/30 is very similar to the previous packaging and remains white with a blue band along the left side of the package.21,23 The previous packaging for NovoLog^® was also white with a blue band.21,23 The current packaging for Novolog^® is now white with an orange band along the left side of the package.21,23 Although color differentiation can help with product recognition, color should not be relied upon as the sole means of identification of the correct drug.23 Pharmacists should also use the drug name and NDC number and other measures to carefully distinguish between insulin formulations when dispensing.21,23 (See Dispensing and Administration Precautions under Warnings/Precautions: General Precautions, in Cautions.)

Dosage

Because of its short duration of action, insulin aspart is used concomitantly with a longer-acting insulin (e.g., isophane [NPH] insulin human, insulin aspart protamine) to meet basal insulin needs in patients with diabetes mellitus and to provide more optimal glycemic control.1,15 Initial total daily insulin requirements may vary and generally range from 0.5-1 units/kg.1 When used in a meal-related subcutaneous injection regimen, 50-70% of the total daily insulin requirement may be provided by insulin aspart and the remainder by an intermediate-acting or long-acting insulin.1 Because of the comparatively rapid onset and short duration of activity of insulin aspart, some patients may require more basal insulin and more total daily insulin to prevent pre-meal hyperglycemia than when using insulin human (regular).1

When insulin aspart is used in external infusion pumps, the initial dosage is based on the total daily insulin dosage of the previous regimen.1 Approximately 50% of the total dosage is given as meal-related injections and the remainder as a basal infusion.1,25 Adjustments in basal insulin injections or higher basal infusion rates may be necessary.1

When insulin aspart in fixed combination with insulin aspart protamine is used as monotherapy in patients with type 1 or 2 diabetes mellitus, an initial total daily dosage of 0.4-0.6 units/kg given in 2 doses (before the morning and evening meal) has been recommended, with subsequent dosage titrated in increments of 2-4 units every 3-4 days to achieve the target fasting plasma glucose.18,19 When the fixed combination of insulin aspart and insulin aspart protamine is given in combination with oral antidiabetic agents, an initial total daily dosage of 0.2-0.3 units/kg has been recommended, with subsequent dosage titration to target glycemic goals.18,19 (See Treatment Goals under Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.) Because of 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.15 The dose of the insulin mixture required to provide adequate glycemic control for one of the meals may result in hypoglycemia or hyperglycemia for the other meal.15 The pharmacodynamic profile of insulin aspart in fixed combination with insulin aspart protamine also may be inadequate for patients who require more frequent meals (e.g., pregnant women).15

When the fixed combination of insulin aspart and insulin aspart protamine is used to replace isophane insulin alone or a biphasic insulin product (e.g., premixed isophane and regular insulin) in patients with adequate glycemic control, the initial dosage of insulin aspart in fixed combination with insulin aspart protamine should be identical to the previous insulin dosage, with subsequent adjustment of dosage as required.18,19 Patients inadequately controlled on isophane insulin may require increases of 10-20% in the dosage of the fixed combination of insulin aspart and insulin aspart protamine during the first week.19 In patients transferring from a multiple-daily-dose regimen consisting of an intermediate-acting (e.g., isophane) insulin and a rapid- or short-acting insulin at mealtimes, the initial dosage of the insulin aspart protamine component of the fixed combination should be same as the dosage of the previously used intermediate-acting insulin.19 Adjustments in the dosage or type of insulin may be needed during illness, emotional or physiologic stress, or changes in meals and exercise.15

Special Populations

In a pharmacokinetic study in a limited number of patients with or without renal impairment (creatinine clearance ranging from normal to less than 30 mL/minute but not requiring hemodialysis) who received a single subcutaneous dose of insulin aspart, peak serum drug concentrations and AUC were not affected; however, only 2 patients with severe renal impairment were studied.1 Similarly, coexisting hepatic impairment (Child-Pugh score 12 or less) did not affect the pharmacokinetics of insulin aspart.1 However, since increased circulating concentrations of insulin have been observed in patients with renal or hepatic failure who were receiving insulin human, careful monitoring of blood glucose and adjustment of insulin aspart dosage may be necessary in such patients.1,10 Dosage requirements for insulin aspart may be reduced in patients with hepatic or renal impairment.1

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer suggests that patients in this age group receive initial dosages of insulin aspart at the lower end of the usual range. 15

Contraindications

Known hypersensitivity to insulin aspart or any ingredient in the formulation.1 Contraindicated during episodes of hypoglycemia.1

Warnings/Precautions

Warnings

Formulation Considerations

Because insulin aspart has a more rapid onset and shorter duration of action than insulin human (regular), administration of insulin aspart should be immediately followed by a meal.1 In addition, a longer-acting insulin is required to maintain adequate glycemic control in patients with type 1 diabetes mellitus.1 Any change in insulin should be made cautiously and only under medical supervision.1,6 Insulin aspart in fixed combination with insulin aspart protamine should not be mixed with any other insulin.15 Patients previously receiving insulin may require a change in dosage if insulin therapy is changed to insulin aspart.1

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, including insulin aspart, and monitoring of blood glucose concentrations is recommended for all patients with diabetes mellitus.1,6,7

Insulin Pumps

Pump or infusion set malfunction or insulin degradation may lead to hyperglycemia and ketosis in a short time period because of the small subcutaneous depot of insulin.1 Because of rapid absorption and short duration of action, such effects may occur when patients are switched from multiple injection therapy or infusion with buffered regular insulin.1 Prompt indentification and correction of hyperglycemia or ketosis is necessary; interim therapy with intermittent subcutaneous injections may be required.1

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Localized allergic reactions (e.g., pruritus, erythema, swelling) at the injection site may develop in patients receiving insulins, including insulin aspart alone or in fixed combination with insulin aspart protamine.1,15 These reactions are relatively minor and usually resolve within a few days to a few weeks but occasionally may require discontinuance of insulin aspart.1 Poor injection technique or irritants in skin cleansing agents may contribute to localized injection site reactions.1,15 As with any insulin, atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injection.1,10,15 Injection site rotation within an area may reduce or prevent these effects.6,10

Generalized hypersensitivity to insulin characterized by rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis has occurred less frequently than localized reactions.1,15 Severe cases of generalized insulin allergy with anaphylaxis may be life-threatening.1,15 In several clinical studies in patients with type 1 and 2 diabetes mellitus receiving insulin human or insulin aspart alone or in fixed combination with insulin aspart protamine, formation of insulin aspart-specific or insulin human-specific antibodies was low in patients receiving either insulin, but among patients receiving insulin aspart-containing regimens, concentrations of cross-reactive antibodies increased after 3-6 months of therapy before returning to near-baseline levels at 12 months.3,24 It was not necessary to increase the dosage of insulin aspart in patients experiencing increased cross-reactive antibodies, and the manufacturer states that the clinical importance of these findings is unknown.1,3 No consistent relationship between antibody formation and glycemic control (as measured by HbA_1c) was observed, and dosage adjustments were not necessary to maintain glycemic control.1,24

Localized reactions and generalized myalgias have been reported with the use of cresol, which is included in the NovoLog^® (insulin aspart) and Novolog^® Mix 70/30 formulations as an excipient.1,15

General Precautions

Hypoglycemia and Hypokalemia

As hypoglycemia and hypokalemia may occur with insulin therapy, care should be taken in patients who are most at risk for the development of these effects, including patients who are fasting, patients with autonomic neuropathy, or patients who are receiving potassium-lowering drugs or drug therapy that may be affected by altered serum potassium concentrations.1 Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death.1 Since IV insulin aspart has a rapid onset of action, increased attention to hypoglycemia and hypokalemia is necessary.1 Serum glucose and potassium concentrations must be monitored closely when insulin aspart or any other insulin is administered IV.1

Dispensing and Administration Precautions

Because of the similarity in names and product packaging between Humalog^® and Humalog^® 75/25, medication errors with these 2 drugs have been noted.22 The manufacturer of Novolog^® Mix 70/30 and Novolog^® has recently implemented color-branded labeling to help prevent dispensing errors.21,23 The current packaging for NovoLog^® Mix 70/30 is very similar to the previous packaging and remains white with a blue band along the left side of the package.21,23 The packaging for NovoLog^® previously was also white with a blue band.21 The current packaging of Novolog^® is now white with an orange band along the left side of the package.21 Although color differentiation can help with product recognition, color should not be relied upon as the sole means of identification of the correct agent.23 Pharmacists should also use the drug name and NDC number and other measures (e.g., matching product name on the prescription to the pharmacy-issued label, separating agents with similar names on pharmacy shelves, counseling patients) to carefully distinguish between insulin formulations when dispensing.21,23 This recent packaging change will not help prevent name confusion errors involving these 2 agents (Novolog^® and Novolog^® Mix 70/30) or other insulin products (e.g., Novolog^® Mix 70/30 and Novolin^® 70/30, or Novolog^® and Novolin^®).23

Dispensing errors involving Novolog^® or Novolog^® Mix 70/30 should be reported to the manufacturer (800-727-6500), the USP Medication Errors Reporting Program (800-233-7767), or the FDA MedWATCH program by phone (800-FDA-1088, 800-FDA-0178 [fax]) or online at [Web].21

Specific Populations

Pregnancy

Category C.1 (See Users' Guide.)

Lactation

It is unknown whether insulin aspart is distributed into milk; caution is advised if used in nursing women.1

Pediatric Use

Safety and efficacy of insulin aspart in fixed combination with insulin aspart protamine not established in children.15 The comparative safety and efficacy of insulin aspart and insulin human (regular) have been demonstrated in a 24-week clinical study in children and adolescents 6-18 years of age with type 1 diabetes mellitus; children also received isophane insulin as the basal insulin supplement.1 Glycemic control (as determined by glycosylated hemoglobin [hemoglobin A_1c, HbA_1c]) was comparable in patients receiving insulin aspart or insulin human.1 In addition, safety and efficacy of insulin aspart were comparable with insulin human in another clinical study in adolescents 12-17 years of age with type 1 diabetes mellitus.8 In comparative study in a limited number of children 2-6 years of age, glycemic control (as measured by HbA_1c, fructosamine) was comparable in children receiving insulin aspart or insulin human.1 As observed in the 6- to 18-year age group, the rates of hypoglycemia in children 2-6 years of age were similar with insulin aspart or insulin human.1 In one pharmacokinetic study, insulin aspart had a more rapid onset and a shorter duration of action when compared with insulin human in a limited number of children and adolescents 6-17 years of a such effects are similar to those observed in adults.1,9

Geriatric Use

Experience in those 65 years of age and older insufficient to determine whether safety differs from younger adults.1 Efficacy of insulin aspart (as measured by HbA_1c) as compared to insulin human appears to be similar in geriatric and younger patients, particularly in patients with type 2 diabetes mellitus.1

Common Adverse Effects

Hypoglycemia, hypersensitivity reactions, lipodystrophy, pruritus, rash, and injection site reactions have been reported with insulin aspart monotherapy.1 In clinical studies, small but persistent elevations in alkaline phosphatase were observed in some patients with type 1 diabetes mellitus who received insulin aspart.1 However, the clinical importance, if any, of these findings has not been established.1,10 Injection site reactions have been reported in 7% of patients receiving insulin aspart in fixed combination with insulin aspart protamine.15 Data from comparative clinical trials evaluating insulin aspart in fixed combination with insulin aspart protamine (Novolog^® Mix 70/30) and insulin human (regular) injection in fixed combination with isophane insulin human (Novolin^® 70/30) did not reveal differences in the frequency of adverse effects between the 2 preparations.15

Drugs Affecting Glycemic Control

Drugs that May Potentiate Hypoglycemic Effects

Angiotensin-converting enzyme (ACE) inhibitors, disopyramide, fibrate derivatives, fluoxetine, monoamine oxidase (MAO) inhibitors, oral antidiabetic agents, propoxyphene, salicylates, somatostatin derivatives (e.g., octreotide), sulfonamide anti-infectives.1

Drugs that May Antagonize Hypoglycemic Effects

Corticosteroids, danazol, diuretics, estrogens and progestins (e.g., oral contraceptives), isoniazid, niacin, phenothiazines, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), thyroid hormones.1

Drugs that May Have a Variable Effect of Glycemic Control

Alcohol, β-adrenergic blocking agents, clonidine, lithium salts, pentamidine.1

Sympatholytic Agents

May decrease or eliminate the signs of hypoglycemia in patients receiving insulin aspart concomitantly with these drugs (e.g., β-adrenergic blocking agents, clonidine, guanethidine, reserpine).1

Description

Insulin aspart (rDNA origin) is a biosynthetic, rapid-acting human insulin analog that is prepared using recombinant DNA technology and genetically modified Saccharomyces cerevisiae .1,2,3 Insulin aspart differs structurally from insulin human by the replacement of proline at position B28 with aspartic acid.1,2 This structural modification results in decreased tendency to form hexamers, more rapid absorption and onset of action, and a shorter duration of action compared with insulin human when given subcutaneously to patients with type 1 diabetes mellitus.1,2,3 Interindividual and intraindividual variation in rate of absorption and consequently, the onset of action of insulins, including insulin aspart alone or in fixed combination with insulin aspart protamine, may occur based on site of injection, tissue blood supply, temperature, and physical activity.1,15

Advice to Patients

Provide information regarding the potential risks and advantages of insulin aspart-containing therapy.1,15

Provide instructions to patient regarding use of subcutaneous insulin infusion devices (e.g., infusion pumps and accessories) and intensive insulin therapy with multiple injections.1

Provide instructions regarding self-monitoring of blood glucose, insulin storage and injection technique, adherence to meal planning, regular physical exercise, periodic hemoglobin A_1c (HbA_1c) monitoring, and management of hypoglycemia or hyperglycemia.1,7,15

Importance of not mixing insulin aspart with crystalline zinc insulin preparations, insulins of animal source, or preparations produced by other manufacturers.1 Importance of using insulin aspart only if solution is clear and colorless with no particles visible; resuspended insulin aspart in fixed combination with insulin aspart protamine must appear uniformly white and cloudy.1,15

Importance of not mixing insulin aspart with other insulins or diluent when used in external subcutaneous infusion pumps.1

Importance of administering insulin aspart or the fixed combination of insulin aspart and insulin aspart protamine within 5-10 minutes or within 15 minutes, respectively, of the start of a meal.1,15

Discuss potential for alterations in insulin requirements in special situations (e.g., illness, emotional disturbances or other stresses).15,16

Importance of informing clinicians of the development of skin reactions (erythema, pruritus, thickened skin) at infusion sites in patients using insulin infusion pumps.1 Importance of selection of a new infusion site, as continued infusion may increase skin reactions and/or alter the absorption of insulin aspart.1

Importance of resumption of subcutaneous insulin injection therapy and of contacting a clinician if pump malfunctions occur and cannot be corrected promptly.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 Importance of women informing clinicians if they are or plan to become pregnant or breast-feed.1,15

Importance of informing patients of other important precautionary information.1,15 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Novo Nordisk Pharmaceuticals Inc.; Novolog^® (insulin aspart [rDNA origin]) injection prescribing information. Princeton, New Jersey; 2005 Oct. 21.

2. Simpson KL, Spencer CM. Insulin aspart. Drugs . 1999; 57:759-65. [PubMed 10353301]

3. Raskin P, Guthrie RA, Leiter L et al. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care . 2000; 23:583-88. [PubMed 10834413]

4. Heinemann L. Insulin aspart: a viewpoint. Drugs . 1999; 57:766.

5. Home P. Insulin aspart: a viewpoint. Drugs . 1999; 57:766-7.

6. American Diabetes Association. Insulin administration. Diabetes Care . 2000; 23(Suppl 1):S86.

7. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care . 2005; 28(Suppl 1):S4-36.

8. Tsalikian E, Silverstein J, Mueller PG. Insulin aspart in adolescent patients with type 1 diabetes. Diabetes . 2000; 49(Suppl 1):Abstract No. 518. [Web]

9. Mortensen HB, Lindholm A, Olsen BS et al. Rapid appearance and onset of action of insulin aspart in pediatric subjects with type 1 diabetes. Eur J Pediatr . 2000;159: 483-8. [PubMed 10923219]

10. Novo Nordisk, Princeton, NJ: Personal communication.

11. Home PD, Lindholm A, Riis A for the European Insulin Aspart Study Group. Insulin aspart vs. human insulin in the management of long-term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabet Med . 2000; 17: 762-70.

12. Raskin P, McGill J, Kilo C et al. Human insulin analog (insulin aspart, Iasp) is comparable to human insulin (HI) in type 2 diabetes. Diabetes . 1999; 48:A355.

13. Bode BW, Strange P. The efficacy, safety, and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes. Diabetes Care . 2001; 24:69-72. [PubMed 11194244]

14. Novo Nordisk Pharmaceuticals. First and only insulin analog approved for pump therapy: new indication for Novo log^® (insulin aspart [rDNA origin] injection offers additional treatment option for insulin users. Princeton, NJ; 2001 Dec 26, Press release from web site. [Web]

15. Novo Nordisk Pharmaceuticals, Inc. Novolog^® Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart injection) suspension prescribing information. Princeton, NJ; 2002 Jun 26.

16. Novo Nordisk Pharmaceuticals, Inc. Novolog^® Mix 70/30 FlexPen^® (70% insulin aspart protamine suspension and 30% insulin aspart injection) prefilled syringe patient information. Princeton, NJ; 2002 Jul.

17. Bode B, Weinstein R, Bell D et al. Comparison of insulin aspart with buffered insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. Diabetes Care . 2002; 25:439-44. [PubMed 11874927]

18. Chapman TM, Noble S, Goa KL. Insulin aspart: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs . 2002; 62:1945-81. [PubMed 12215068]

19. Novo Nordisk. Insulin analogue adult treatment guidelines (undated). Princeton, NJ. Available from website. Accessed November 21, 2002. [Web]

20. Bode BW, Strange P. Efficacy, safety, and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes. Diabetes Care . 2001; 24:69-72. [PubMed 11194244]

21. Justice N. Dear pharmacist letter: dispensing error alert. Princeton, NJ: Novo Nordisk; 2005 Aug. 26.

22. Institute for Safe Medication Practices. Proliferation of insulin combination prodcuts increases opportunity for errors. 2002 Nov. 27. Available from website. Accessed Nov. 28, 2005. [Web]

23. Institute for Safe Medication Practices. New packaging labeling for NovologMix 70/30 and Novolog. 2005 Oct. Available from website. Accessed Nov. 28, 2005. [Web]

24. Lindholm A, Jensen LB, Home PD et al. Immune response to insulin aspart and biphasic insulin aspart in people with type 1 and type 2 diabetes. Diabetes Care . 2002; 25:876-82. [PubMed 11978684]

25. Powers A. Diabetes mellitus. In: Kasper DL, Fauci A, Longo DL eds. Harrison's principles of internal medicine. New York: McGraw-Hill; 2005:2174.

26. Novo Nordisk. Innovo^®—It remembers. Frequently asked questions. Princeton, NJ. 2005. Available from website. Accessed Dec. 1, 2005. [Web]

27. LifeScan. Induo^®: storage and handling. Milpitas, CA. 2005. Available from website. [Web]

28. LifeScan. OneTouch^® InDuo^®: blood glucose monitoring and insulin dosing system. Milpitas, CA. Undated. Available from website. [Web]