Apidra

A

Generic Name: Insulin Glulisine
Class: Insulins
Chemical Name: [3B-L-Lysine,29B-L-glutamic acid] insulin (human)
Molecular Formula: C258H384N64O78S6
CAS Number: 207748-29-6

Introduction

Antidiabetic agent; rapid-acting human insulin analog prepared using recombinant DNA technology and special laboratory strain of nonpathogenic Escherichia coli (K12).1 2 7

Uses for Apidra Diabetes Mellitus

Treatment of type 1 or type 2 diabetes mellitus in adults who require a rapid-acting insulin for control of hyperglycemia.1 2 3 4

Used in conjunction with a longer-acting insulin (e.g., isophane [NPH] insulin human, insulin glargine), except when administered via an external controlled-infusion device (pump).1 2 4 6 7

At least as effective for glycemic control as insulin human (regular) or insulin lispro.1 3 4 6

May provide greater convenience compared with insulin human (regular) in timing of insulin injections in relation to meals; clinical relevance of this difference remains to be established.3 4 6

Used by IV infusion in appropriately monitored patients;1 American Diabetes Association (ADA) states that insulin glulisine offers no advantage over regular crystalline insulin in patients who require IV insulin.

Apidra Dosage and Administration Administration

Administer by sub-Q injection, continuous sub-Q infusion, or IV infusion.1 2 8

Sub-Q Injection

For solution and drug compatibility information, see Compatibility under Stability.

When used as a mealtime insulin to control postprandial hyperglycemia, administer within 15 minutes before a meal or 20 minutes after starting a meal.1 2 6 8

Administer by sub-Q injection using a conventional insulin syringe or an insulin injection pen (e.g., OptiClik) using BD ultra-fine needles.1 2 Apidra 3-mL cartridges are intended for use with the OptiClik injection pen; use of other injection pens with the cartridge may lead to inaccurate dosing.1 2 9

Consult accompanying labeling for proper assembly, administration, and care of the injection pen.2 If the OptiClik device malfunctions, may withdraw insulin glulisine from the cartridge system into a U-100 insulin syringe and inject.1

Inject into abdominal wall, thigh, or upper arm.1 2 6 8 Follow a planned rotation of injection sites within an injection area.1 2 8

Sub-Q Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Administer by continuous sub-Q 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 2 8

Replace infusion set (reservoir, tubing, and catheter) at least every 48 hours; replace insulin glulisine in the reservoir and select new infusion site.1

Consult manufacturer’s labeling for specialized administration techniques (e.g., length of infusion, frequency of changing infusion sets) or other details specific to insulin glulisine.1 Consult manual provided by manufacturer of sub-Q infusion device for additional information on general use of the pump.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion in a setting that allows appropriate clinical and laboratory monitoring.1 (See Hypoglycemia and Hypokalemia under Cautions.)

Dilution

For IV infusion, dilute in 0.9% sodium chloride injection to a concentration of 1 unit/mL.1

Dosage

Dosage of insulin glulisine is expressed in terms of USP units.1 a

Insulin glulisine and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity.1 6 7 8 (See Pharmacokinetics.)

More rapid onset and shorter duration of action than insulin human (regular).1 2 7 8 May require a longer-acting insulin or insulin infusion therapy to maintain adequate glycemic control.1 7 8

Individualize dosage based on blood glucose determinations to obtain optimum therapeutic effect.1 8 No specific dosage recommendations by the manufacturer.1

Whenever possible, patients should self-monitor blood glucose concentrations.1 2 8

Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.

Make any dosage change cautiously and only under medical supervision.1 2 a Changes in insulin therapy (e.g., strength, timing of dosing, manufacturer, type, method of administration, or species [animal insulins no longer commercially available in US]) may necessitate adjustments in dosage of insulin glulisine or concomitant antidiabetic agents.1 2 a

Insulin dosage adjustment may be necessary if patient changes usual physical activity or meal plan, or during times of illness, emotional disturbances, or stress.1 2

Adults Diabetes Mellitus Type 1 Sub-Q Injection

Usually, initial total insulin dosages range from 0.2–1 units/kg daily.

As part of a meal-related 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.

Sub-Q Infusion

When used in external infusion pumps, a portion of the total dosage is given as meal-related injections, with the remainder as a basal infusion.8 Individualize dosage; adjust dosage regularly based on blood glucose determinations.1

Type 2 Sub-Q Injection

In patients not controlled on intermediate-acting or long-acting insulin, some clinicians suggest initiating preprandial therapy with a rapid-acting insulin (e.g., insulin glulisine), with the preprandial injection comprising 40–50% of the total insulin dosage and the remainder (50–60%) given as a basal insulin.5

Sub-Q Infusion

When used in external infusion pumps, a portion of the total dosage is given as meal-related injections, with the remainder as a basal infusion.8 Individualize dosage; adjust dosage regularly based on blood glucose determinations.1

Special Populations Hepatic Impairment

Dosage reduction may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Dosage reduction may be required; carefully monitor blood glucose concentrations and adjust dosage as necessary.1 (See Elimination: Special Populations, under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Lactation

Dosage adjustments may be required.1

Cautions for Apidra Contraindications

Known hypersensitivity to insulin glulisine or any ingredient in the formulation.1 2

Hypoglycemic episodes.1 7

Warnings/Precautions Warnings Hypoglycemia

Most common adverse effect of insulins.1 Blood glucose concentration monitoring is recommended for all diabetic patients.1 Hypoglycemic timing may differ among various insulin formulations and may change when the treatment regimen or timing of dosing of the insulins is changed.b

Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.1 Early warning signs of hypoglycemia may be diminished or absent in patients with long-standing diabetes mellitus, diabetic neuropathy, intensified diabetes control, and/or those receiving drugs such as ?-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia.1 a Severe hypoglycemia (including loss of consciousness) may occur prior to patient’s awareness.1

Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes. Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.

Insulin Pumps

For solution and drug compatibility information, see Compatibility under Stability. For pump compatibility, see Sub-Q Infusion under Administration in Dosage and Administration.

Because of rapid onset and shorter duration of action of insulin glulisine compared to insulin human, risk of hyperglycemia and ketosis in a shorter time period if pump or infusion set malfunctions or if insulin degradation occurs.1

Prompt identification and correction of hyperglycemia or ketosis is necessary; may require interim therapy with sub-Q injections until problems with pump are corrected.1

Sensitivity Reactions Hypersensitivity Reactions

Possible localized allergic reactions (e.g., pruritus, erythema, swelling) at injection site; usually resolve within a few days to a few weeks.1 a In some patients, may be related to other factors (e.g., irritants in skin cleaning agent, poor injection technique).1

Generalized hypersensitivity reactions (e.g., rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis, anaphylaxis) reported less frequently than localized reactions, but may be life-threatening.1 2

Localized reactions and generalized myalgias reported with use of m-cresol, an excipient in the formulation.1

Antibody Formation

Can stimulate transient formation of antibodies to insulin that may cross-react with insulin glulisine or HbA1c insulin human.1 No correlation found between antibody concentration and changes in HbA1c, insulin doses, or incidence of hypoglycemia.1 8

General Precautions Hypoglycemia and Hypokalemia

Following IV administration, closely monitor glucose and potassium concentrations to avoid potentially fatal hypoglycemia or hypokalemia.1 (See Hypoglycemia under Cautions.)

Lipodystrophy

Atrophy or hypertrophy of subcutaneous fat tissue may occur at injection sites and may delay insulin absorption;1 injection site rotation may reduce or prevent these effects.2

Specific Populations Pregnancy

Category C.1

Lactation

Not known whether insulin glulisine is distributed into milk; use caution in nursing women.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 9 (See Absorption: Special Populations, under Pharmacokinetics.)

Geriatric Use

No substantial differences in safety and efficacy in those ?65 years of age relative to younger adults; however, possibility exists of greater sensitivity in some geriatric individuals.1

Common Adverse Effects

Hypoglycemia,1 7 8 systemic hypersensitivity,1 4 7 8 injection site reaction.1 3 4 7 8

Interactions for Apidra

Many drugs affect glucose metabolism; if such drugs are used concomitantly, may require insulin dosage adjustment and careful monitoring.1

Specific Drugs Drugs That May Potentiate Hypoglycemic Effects17

ACE inhibitors

Disopyramide

Fibrate derivatives

Fluoxetine

MAO inhibitors

Oral antidiabetic agents

Pentoxifylline

Propoxyphene

Salicylates

Sulfa anti-infectives

Drugs That May Antagonize Hypoglycemic Effects17

Antipsychotics, atypical (e.g., clozapine, olanzapine)

Corticosteroids

Danazol

Diazoxide

Diuretics

Estrogens and progestins (e.g., oral contraceptives)

Glucagon

HIV protease inhibitors

Isoniazid

Phenothiazines

Somatropin

Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline)

Thyroid hormones

Drugs That May Have a Variable Effect on Glycemic Control17

?-Adrenergic blocking agents

Alcohol

Clonidine

Lithium salts

Pentamidine

Drugs That May Reduce or Eliminate Signs of Hypoglycemia (Sympatholytic Agents)17

?-Adrenergic blocking agents

Clonidine

Guanethidine

Reserpine

Apidra Pharmacokinetics Absorption Bioavailability

Following sub-Q injection, absorption is rapid; faster than that of insulin human (regular).1 7 8

Following sub-Q injection, absolute bioavailability is approximately 70%.1

Substantial interindividual and intraindividual variation may occur based on site of injection, method of administration, tissue blood supply, temperature, and physical activity.1 8

Atrophy or hypertrophy of subcutaneous fat tissue at the injection site1 2 may delay absorption.1

Onset

Following sub-Q injection, insulin glulisine has shorter onset of action than insulin human (regular).1

Duration

Following sub-Q injection, duration is shorter than that of insulin human insulin (regular).1 3 7 8

Special Populations

Relative differences in pharmacokinetics between insulin glulisine and insulin human (regular) in type 1 diabetic children 7–16 years of age similar to the relative differences observed in adults.1 (See Pediatric Use under Cautions.)

Distribution Extent

Following IV administration, distribution similar to that of insulin human (regular).1

Not known whether insulin glulisine is distributed into milk.1

Elimination

Following sub-Q injection, elimination more rapid than that of insulin human (regular).1 8

Following IV administration, elimination similar to that of human insulin (regular).1

Half-life

Sub-Q administration: 42 minutes.1 7 8

IV administration: 13 minutes.1 7 8

Special Populations

Reduced clearance reported in nondiabetic patients with moderate or severe renal impairment.1 (See Renal Impairment under Dosage and Administration.)

Effects of hepatic impairment not evaluated; however, possible increased circulating concentrations of insulin, reduced capacity for gluconeogenesis, and reduced insulin metabolism, based on observations with other insulins in patients with hepatic dysfunction.1 (See Hepatic Impairment under Dosage and Administration.)

Stability Storage Parenteral Injection

Unopened vials and cartridges: 2–8°C.1 2 Protect from light.1 2 Do not freeze; discard if solution has been frozen.1 2

Opened (in-use) vials: <25°C for ?28 days.1 Protect from direct heat and light.1

When diluted for IV administration, stable at room temperature for 48 hours.1

OptiClik opened cartridges: <25°C away from direct heat and light.1 Discard opened cartridge system after 28 days.1 Do not refrigerate OptiClik system, with or without cartridges.1

Infusion sets (reservoirs, tubing, and catheters): Discard infusion set and any insulin glulisine in the reservoir after 48 hours (or less) of use.1 Discard if exposed to >37°C.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

When used in an external infusion pump, do not mix insulin glulisine with other insulins or diluents.1

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

Solution Compatibility

Compatible with 0.9% sodium chloride injection.1

Incompatible with dextrose or Ringer’s injection; other IV diluents not studied and not recommended.1

Drug Compatibility

Compatible with isophane insulin human; incompatible with other insulin preparations.1 2

If mixed with isophane insulin human for sub-Q injection, draw insulin glulisine into the syringe first.1 8 Administer immediately after mixing; do not administer such mixtures IV.1

ActionsActions

Pharmacologic effects comparable to those of insulin human;1 8 stimulates peripheral glucose uptake by tissues (e.g., skeletal muscle, fat), inhibits hepatic glucose production, inhibits lipolysis, and enhances protein synthesis.1

More rapid onset and shorter duration of action than insulin human (regular) following sub-Q administration.1 3 7 8

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 sub-Q 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 sub-Q infusion pumps.1 2

Importance of administering insulin glulisine ?15 minutes before a meal or ?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 BP, wheezing, whole body rash, fast pulse, sweating).2

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

Importance of resumption of sub-Q 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 disease.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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Insulin Glulisine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

100 units/mL

Apidra (with m-cresol; available as 3-mL cartridges, OptiClik prefilled pen, and 10-mL vials)

Sanofi-Aventis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Apidra 100UNIT/ML Solution (SANOFI-AVENTIS U.S.): 10/$109.99 or 30/$307.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions July 01, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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. [IDIS 519852] [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 from website. Accessed 2008 Mar 17.

a. AHFS drug information 2008. McEvoy GK, ed. Insulins general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3196-3207.

b. Novo Nordisk. Levemir (insulin detemir [rDNA origin] injection prescribing information. Princeton, NJ; 2007 May 16.

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Apidra

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