AHFS Class:

• Rapid-acting Insulins 68:20.08.04

Generic Name(s):

• Insulin Glulisine

Chemical Name:

• [3^B- L -Lysine,29^B- L -glutamic acid] insulin (human)

Molecular Formula:

• C₂₅₈H₃₈₄N₆₄O₇₈S₆

Insulin glulisine is a biosynthetic (rDNA origin), rapid-acting human insulin analog.1

Diabetes Mellitus

Insulin glulisine is a rapid-acting insulin analog that is used to control hyperglycemia in the management of diabetes mellitus.1,3,4 Insulin glulisine generally is used in conjunction with a longer-acting insulin (except when administered via an external controlled-infusion device [pump]) to provide basal insulin needs.1

Insulin glulisine appears to be at least as effective for glycemic control as insulin human (regular) or insulin lispro.1,3,4,6 In addition, insulin glulisine may provide improved treatment convenience compared with insulin human (regular) by more closely mimicking endogenous insulin response to meals; the clinical relevance of this difference remains to be established.3,4,6

In a randomized, open-label study designed to establish the efficacy and safety of preprandial (0-15 minutes before a meal) injections of insulin glulisine compared with insulin lispro for the treatment of type 1 diabetes mellitus, insulin glulisine was noninferior to insulin lispro in improving glycemic control (as determined by glycosylated hemoglobin [HbA_1c]).1,4 The proportion of patients achieving an HbA_1c of 7 or less at study end point was 35.6 and 34.5% for insulin glulisine and insulin lispro, respectively.4 Patients in this study also received insulin glargine once daily as the basal insulin.1,4 Patients receiving insulin lispro required slightly higher total daily dosages of insulin because of increased basal insulin requirements.4 The rates of hypoglycemia, including symptomatic, severe (requiring the assistance of another person), and nocturnal hypoglycemia, were comparable for the 2 treatment groups.1,4

The safety and efficacy of flexible mealtime administration of insulin glulisine for the treatment of type 1 diabetes mellitus are based principally on the results of a study comparing pre-meal or post-meal administration of insulin glulisine with pre-meal administration of insulin human (regular).1,6,7 In a large, randomized, comparative study, insulin glulisine administered within 15 minutes before or within 20 minutes after a meal was noninferior to insulin human (regular) administered 30-45 minutes prior to meals in improving glycemic control (as determined by HbA_1c), the primary clinical end point.1,6 Patients in this study also received insulin glargine (once daily at bedtime) as the basal insulin.1,6 Rates of hypoglycemia, including symptomatic, severe (requiring the assistance of another person), and nocturnal hypoglycemia, were similar across treatment groups.1,6

In a randomized, open-label trial designed to compare the efficacy and safety of insulin glulisine to insulin human (regular) in patients with type 2 diabetes mellitus, insulin glulisine was noninferior to insulin human (regular) in improving glycemic control (as determined by HbA_1c), the primary clinical end point.1,3,7 The proportion of patients achieving an HbA_1c of 7 or less at study end point was 53.5 and 50.6% for insulin glulisine and insulin human (regular), respectively.3 Patients in this study also received isophane insulin human as the basal insulin, and more than 50% of patients continued therapy with an oral antidiabetic agent during the study.1,3 Total daily insulin dosages (basal and rapid- or short-acting insulins) were similar in both treatment groups.1,3 The rates of hypoglycemia, including symptomatic, severe (i.e., requiring the assistance of another person), and nocturnal hypoglycemia, were comparable for the 2 treatment groups.1,3

Insulin glulisine also is administered by continuous subcutaneous infusion using an external controlled-infusion pump (e.g., Disetronic^® H-Tron plus V100; D-Tron^®; MiniMed^® models 506, 507, 507c, and 508) in patients with diabetes mellitus.1 Limited data in patients with type 1 diabetes mellitus suggest that continuous subcutaneous infusion of insulin glulisine provides glycemic control (as measured by HbA_1c) that is noninferior to that provided by continuous subcutaneous infusion of insulin aspart.1,8 These data also indicate a similar incidence of severe hypoglycemia and catheter occlusions among patients receiving insulin glulisine or insulin aspart.1,8

Insulin glulisine also is administered by IV infusion for glycemic control in a setting that allows appropriate clinical and laboratory monitoring.1 (See Warnings: Hypoglycemia, under Warnings/Precautions in Cautions.)

General

Dosage of insulin glulisine is expressed in units.1 Each unit of insulin glulisine is approximately equal to 0.0349 mg of the drug.1

Dosage of insulin glulisine must be based on the results of blood glucose determinations and must be carefully individualized to obtain optimum therapeutic effect.1,8 Glucose monitoring is recommended for all patients with diabetes mellitus.1 Whenever possible, patients should self-monitor blood glucose concentrations.1,2 Because of its short duration of action, insulin glulisine used as a mealtime insulin is given concomitantly with a longer-acting insulin (e.g., insulin glargine, isophane insulin human) to meet basal insulin needs and to provide more optimal glycemic control.1,4,7

Administration

Insulin glulisine is administered by subcutaneous injection using a conventional insulin syringe or an insulin injection pen (e.g., OptiClik^®) using BD ultrafine needles.1,2 The manufacturer states that the OptiClik^® 3-mL cartridge systems are intended for use with the OptiClik^® reusable injection pen.1,2,9,10 The OptiClik^® disposable cartridge systems cannot be used with other insulin pen devices.2,9,10 Use of other injection pens with these cartridge systems may lead to inaccurate dosing.1,2

When the OptiClik^® injection pen is used for subcutaneous injection of insulin glulisine, the accompanying labeling should be consulted for proper methods of assembly, administration, and care.2 If the OptiClik^® device malfunctions, the insulin glulisine in the cartridge system may be withdrawn into a U-100 insulin syringe and injected.1

When used as a mealtime insulin to control postprandial hyperglycemia, insulin glulisine is administered within 15 minutes before a meal or 20 minutes after starting a meal by subcutaneous injection into the abdominal wall, thigh, or upper arm.1,2,6,8 A planned rotation of injection sites and injection sites within an area should be followed.1,8

Insulin glulisine administered by subcutaneous injection may be mixed with isophane insulin human; the drug should not be mixed with any other type of insulin.1,2 Whenever insulin glulisine is mixed with isophane insulin human, insulin glulisine should be drawn into the syringe first.1,2,8 The insulin mixture should be administered immediately after mixing; such mixtures should not be administered IV.1,8

Insulin glulisine also is administered by continuous subcutaneous infusion into the abdominal wall using an external controlled-infusion device (e.g., Disetronic^® H-Tron plus V100; D-Tron^®; MiniMed^® models 506, 507, 507c, and 508).1,8 When used in an external infusion pump, insulin glulisine should not be diluted or mixed with any other insulins.1,2 For information on the stability of insulin glulisine in external infusion pumps, see Chemistry and Stability: Stability, in the Insulins General Statement 68:20.08.

Insulin glulisine also is administered by IV infusion for glycemic control under appropriate medical supervision in a clinical setting.1 (See Warnings: Hypoglycemia, in Cautions.) When administered IV, insulin glulisine should be diluted to a concentration of 1 unit/mL in 0.9% sodium chloride injection.1 Insulin glulisine is not compatible with, and should not be diluted in, dextrose or Ringer's injection.1 The manufacturer states that use of use of IV diluents other than 0.9% sodium chloride injection has not been studied and is not recommended.1 The manufacturer recommends use of polyvinyl chloride Viaflex^® infusion bags and polyvinyl chloride tubing with a dedicated infusion line; compatibility with other bags or tubing has not been established.1,9

Diluted solutions of insulin glulisine for IV infusion should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 Only clear and colorless solutions should be used; solutions should be discarded if they are cloudy or contain particulate matter.1

Dosage

Insulin glulisine and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity (as determined following IV administration).1,7,8

Diabetes Mellitus

Because of its short duration of action, insulin glulisine when used as a mealtime insulin is given concomitantly with a longer-acting insulin (e.g., insulin glargine, isophane insulin human) to meet basal insulin needs and to provide more optimal glycemic control.1,7,8 Initial total daily insulin dosages in adults and children with type 1 diabetes mellitus range from 0.2-1 units/kg. When used in a meal-related subcutaneous insulin regimen, basal insulin requirements (e.g., using insulin detemir, insulin glargine) usually comprise 40-60% of the total daily insulin dosage, with the remainder given preprandially as rapid- or short-acting insulin.

In patients with type 2 diabetes mellitus who are not controlled on intermediate-acting or long-acting insulin, some clinicians suggest initiating preprandial therapy with a rapid-acting insulin, with the preprandial injection comprising 40-50% of the total insulin dosage and the remainder given as a basal insulin.5

When insulin glulisine is used in external infusion pumps, a portion of the total dosage is administered as meal-related injections and the remainder as a basal infusion.8

For additional information on monitoring and management of insulin therapy, see Dosage and Administration: Dosage, in the Insulins General Statement 68:20.08.

Special Populations

In a pharmacokinetic study in a limited number of nondiabetic patients with or without renal impairment (creatinine clearance ranging from normal to less than 30 mL/minute), increased insulin glulisine exposure and reduced drug clearance were observed in patients with moderate to severe renal impairment.1 Careful monitoring of blood glucose concentrations and reduction in the dosage of insulin glulisine may be necessary in such patients.1

The effects of hepatic impairment on the pharmacokinetics of insulin glulisine have not been evaluated.1 However, increased circulating concentrations of insulin have been observed in patients with liver failure who were receiving insulin human.1 Based on observations with other insulins, insulin glulisine requirements may be decreased due to a reduced capacity for gluconeogenesis and reduced insulin metabolism.1 Careful monitoring of blood glucose concentrations and reduction in the dosage of insulin glulisine may be necessary in such patients.1

Contraindications

Known hypersensitivity to insulin glulisine or to any ingredient in the formulation.1 Contraindicated during episodes of hypoglycemia.1,7

Warnings/Precautions

Warnings

Formulation Considerations

Because of the rapid onset and short duration of action of insulin glulisine, patients may require a longer-acting insulin or continuous subcutaneous insulin infusion pump therapy to maintain adequate glycemic control.1,7 Any change in insulin should be made cautiously and only under medical supervision.1,2 Changes in insulin strength, timing of dosing, type, method of administration, and/or species source or method of manufacture may necessitate a change in insulin dosage.1,2 Concomitant oral antidiabetic therapy may need to be adjusted.1,2

Hypoglycemia

Hypoglycemia is the most common adverse effect of insulins, including insulin glulisine, and monitoring of blood glucose concentrations is recommended for all patients with diabetes mellitus.1 Timing of hypoglycemia may differ among various insulin formulations.1 In comparative studies, the incidence of severe hypoglycemic reactions with insulin glulisine was similar to that with insulin human (regular) or insulin lispro.1,3,4 IV administration of insulin glulisine requires strict medical supervision and appropriate monitoring of glucose and potassium concentrations to avoid hypoglycemia and hypokalemia.1 For more information on the symptoms associated with hypoglycemia, see Hypoglycemia under Cautions: Endocrine and Metabolic Effects, in the Insulins General Statement 68:20.08.

Insulin Pumps

When used in an external infusion pump, insulin glulisine should not be diluted or mixed with any other insulins.1,2 Because of the more rapid onset and shorter duration of action of insulin glulisine compared with insulin human, malfunction of the pump or infusion set or insulin degradation may lead to hyperglycemia and ketosis in a shorter time period.1,2 Potential problems with external insulin infusion pumps include pump malfunction, infusion set occlusion, leakage, catheter disconnection or kinking, and degraded insulin.1,8 Prompt identification and correction of hyperglycemia or ketosis is necessary; interim therapy with intermittent subcutaneous injections may be required if problems with the continuous subcutaneous infusion pump cannot be promptly corrected.1,2

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Localized allergic reactions (e.g., pruritus, erythema, swelling) at the injection site may develop in patients receiving insulin, including insulin glulisine.1 These reactions are relatively minor and usually resolve within a few days to a few weeks.1 Poor injection technique or irritants in skin cleansing agents may contribute to localized injection site reactions.1 As with any insulin, atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injection.1,2 Injection site rotation within an area may reduce or prevent these effects.2

Generalized hypersensitivity to insulin characterized by rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis has occurred less frequently than localized reactions.1 Severe cases of generalized insulin allergy with anaphylaxis may be life-threatening.1 In a clinical study in patients with type 1 diabetes mellitus receiving insulin human (regular) or insulin glulisine, concentrations of cross-reactive antibodies to either insulin remained near baseline levels during the first 6 months of therapy before decreasing during the following 6 months.1,8 In a study in patients with type 2 diabetes mellitus, the concentrations of cross-reactive insulin antibodies increased in patients receiving either insulin glulisine or insulin human (regular) during the first 9 months of the study, then decreased in patients receiving insulin glulisine and remained stable in patients receiving insulin human (regular).1,8 No consistent relationship between antibody formation and glycemic control (as measured by HbA_1c), insulin dosage adjustments, or incidence of hypoglycemia was observed.1,8

Localized reactions and generalized myalgias have been reported with the use of cresol, which is included as an excipient in the Apidra^® (insulin glulisine) formulation.1

General Precautions

Concurrent Illness

Insulin requirements may be altered during illness, emotional disturbances, or stress.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.) Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery.1

Lactation

Not known whether insulin glulisine is distributed into milk.1 Caution is advised if used in nursing women.1 Diabetic women who are lactating may require adjustments in insulin dosage, meal plans, or both.1

Pediatric Use

Safety and efficacy not established in children younger than 18 years of age.1,9

Geriatric Use

No substantial differences in safety (i.e., incidence of hypoglycemia) and efficacy (i.e., changes in HbA_1c) relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Careful monitoring of blood glucose concentrations and reduction in the dosage of insulin glulisine may be necessary in patients with hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Renal Impairment

Careful monitoring of blood glucose concentrations and reduction in the dosage of insulin glulisine may be necessary in patients with renal impairment.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Hypoglycemia.1,3,7,8 Systemic hypersensitivity1,4,7,8 and injection site reactions1,3,4,7,8 also have been reported.1,7,8

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, pentoxifylline, propoxyphene, salicylates, sulfonamide anti-infectives.1

Drugs that May Antagonize Hypoglycemic Effects

Atypical antipsychotic agents (e.g., olanzapine, clozapine), corticosteroids, danazol, diazoxide, diuretics, estrogens and progestins (e.g., oral contraceptives), glucagon, isoniazid, phenothiazines, protease inhibitors, 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

Signs of hypoglycemia may be decreased or absent in patients receiving insulin glulisine concomitantly with these drugs (e.g., β-adrenergic blocking agents, clonidine, guanethidine, reserpine).1

Description

Insulin glulisine is a biosynthetic, rapid-acting insulin human analog that is prepared using recombinant DNA technology and a special laboratory strain of nonpathogenic Escherichia coli (K12).1,7 Insulin glulisine differs structurally from insulin human by the replacement of asparagine at position 3 on the B chain with lysine and by replacement of lysine at position 29 on the B chain with glutamic acid.1,6,8 These structural modifications result in a decreased tendency to form hexamers, improved monomer stability, and increased rate of absorption.7,8

Following subcutaneous administration, insulin glulisine has a more rapid onset and shorter duration of action compared with insulin human (regular).1,3,7,8 Insulin glulisine has pharmacologic effects comparable to those of insulin human.1,8 (See Pharmacology in the Insulins General Statement 68:20.08.) Results of clinical trials indicate that the glucose-lowering effect of insulin glulisine is approximately the same as that of insulin human on a unit-for-unit basis.1,6,7

Interindividual and intraindividual variation in rate of absorption and consequently, the onset of action of insulins, including insulin glulisine, may occur based on site of injection, method of administration, tissue blood supply, temperature, and physical activity.1,8 (See Warnings: Formulation Considerations, under Warnings/Precautions in Cautions.)

Advice to Patients

Provide copy of manufacturer's information for patients.1

Importance of strict adherence to manufacturer's instructions regarding assembly, administration, and care of specialized delivery systems, such as insulin pens or pumps.1,2

Provide instructions regarding self-monitoring of blood glucose, insulin storage and injection technique, adherence to meal planning, physical exercise, blood glucose monitoring, and management of hypoglycemia or hyperglycemia.1,2

Importance of not mixing insulin glulisine for subcutaneous injection with insulin preparations other than isophane insulin human.1,2 When mixing with isophane insulin human, importance of drawing insulin glulisine into the syringe first.1,2,8 Importance of using insulin glulisine only if solution is clear and colorless with no visible particles.1,2

Importance of not mixing insulin glulisine with other insulins or diluents when used in external subcutaneous infusion pumps.1,2

Importance of administering insulin glulisine within 15 minutes before a meal or within 20 minutes after the start of a meal.1,2,8

Importance of changing insulin dosage with caution and only under medical supervision.1,2 Discuss potential for alterations in insulin requirements in special situations (e.g., illness, emotional disturbances or other stresses, concomitant agents that alter glycemic control).1,2 Discuss potential for alterations in insulin requirements as a result of changes in physical activity, inadequate or missed doses, inadvertent administration of incorrect doses, inadequate food intake, or skipped meals.1,2,8

Importance of providing instructions on safe disposal of needles.2

Importance of informing clinicians of recurrent or persistent skin reactions (erythema, pruritus, thickened skin, skin depression or atrophy) at injection or infusion sites.1,2 Importance of selecting a new infusion or injection site if such reactions occur.1,2

Importance of informing clinicians of the development of generalized hypersensitivity reactions (shortness of breath, low blood pressure, wheezing, whole body rash, fast pulse, sweating).2

Importance of wearing a medical alert identification, carrying ample insulin and supplies when traveling, and having carbohydrates (sugar or candy) on hand for emergencies.2

Importance of resumption of subcutaneous injections of insulin glulisine with a syringe and of contacting a clinician if pump malfunctions occur and cannot be corrected promptly.1,2

Importance of contacting a clinician if self-monitored blood glucose concentrations are consistently high.2

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as concomitant alcohol ingestion.1,2

Importance of informing clinicians of concomitant illnesses, including hepatic or renal problems.2

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,2

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

Additional Information

Overview^® (see Users Guide). For additional information on this drug 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. Sanofi-Aventis. Apidra^® (insulin glulisine [rDNA origin]) injection prescribing information. Bridgewater, NJ; 2007 Apr.

2. Sanofi-Aventis. Apidra^® (insulin glulisine [rDNA]) injection patient information. Bridgewater, NJ; 2007 Apr.

3. Dailey G, Rosenstock J, Moses RG et al. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care . 2004; 27:2363-8. [PubMed 15451901]

4. Dreyer M, Prager R, Robinson A et al. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Horm Metab Res . 2005; 37:702-7. [PubMed 16308840]

5. Mayfield JA, White RD. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician . 2004; 70:489-500, 511-2. [PubMed 15317436]

6. Garg SK, Rosenstock J, Ways K . Optimized basal-bolus insulin requirements in type 1 diabetes: insulin glulisine versus regular human insulin in combination with basal insulin glargine. Endocr Pract . 2005; 11:11-7. [PubMed 16033730]

7. Robinson DM, Wellington K. Insulin glulisine. Drugs . 2006; 66:861-9. [PubMed 16706558]

8. Gabry KE. Insulin glulisine injection, Apidra^®. Summary basis of approval: medical review. NDA number: 21-629. Rockville, MD: US Food and Drug Administration; 2004 Apr 16.

9. Sanofi-Aventis, Bridgewater, NJ: Personal communication.

10. Sanofi-Aventis. Getting to know your Opticlik^® pen: Opticlik^® and its parts. Bridgewater, NJ; 2006 Feb. Available at [Web]. Accessed 2008 Mar 17.