Insulin Glulisine

Pharmacologic Category

Insulin, Rapid-Acting

Dosing: Adult

Note: Insulin glulisine is a rapid-acting insulin analog. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision.

Diabetes mellitus, type 1: SubQ:

Note: Insulin glulisine must be used concomitantly with intermediate- or long-acting insulin (ie, multiple daily injection regimen) or in a continuous subcutaneous insulin infusion pump. The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

General insulin dosing:

Initial total daily dose: ~0.4 to 0.5 units/kg/day; conservative initial doses of 0.2 to 0.4 units/kg/day may be considered to avoid the potential for hypoglycemia; higher initial doses may be required in patients who are obese, sedentary or presenting with ketoacidosis (AACE/ACE [Handelsman 2015]; ADA 2019).

Usual total daily dose maintenance range: 0.4 to 1 units/kg/day in divided doses (ADA 2019)

Division of total daily dose (multiple daily injections):

Basal insulin: Generally, 40 to 50% of the TDD is given as basal insulin (intermediate- or long-acting) in 1 to 2 daily injections (AACE/ACE [Handelsman] 2015]; ADA 2019).

Prandial insulin: The remaining portion (ie, 50 to 60%) of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, glulisine, aspart, lispro, insulin for inhalation) or short-acting (regular) insulin (AACE/ACE [Handelsman 2015]; ADA 2019).

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.

Diabetes mellitus, type 2 (AACE/ACE [Garber 2019]; ADA 2019): SubQ:

Initial:4 to 5 units or 10% of the basal insulin dose administered before the largest meal of the day.

Note: Stepwise addition of prandial insulin starting with a single meal and progressing to 2 or more meals as needed every 3 months is associated with a lower risk of hypoglycemia and increased patient satisfaction compared with immediate introduction of a full basal-bolus regimen. Insulin glulisine (ie, a rapid-acting insulin) is usually given in addition to a regimen that includes basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir; or an intermediate-actin insulin such as NPH) and metformin +/- other noninsulin agents. Consider reducing the total daily dose by 4 units or 10% of the basal insulin dose if HbA_1c is <8% when initiating prandial insulin.

Dosage adjustment:

To reach self-monitoring glucose target: Adjust dose by 10% to 15% or 1 to 2 units twice weekly.

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 10% to 20%; for severe hypoglycemia (ie, requiring assistance from another person or blood glucose <40 mg/dL), reduce dose by 20% to 40%.

HbA_1c still not controlled despite titrations to reach glycemic targets: One option is to advance to ‘basal-bolus’ (ie, insulin glulisine administered before ≥2 meals per day) in addition to basal insulin and usually given in addition to metformin +/- other noninsulin agents.

Patients with diabetes receiving enteral feedings (ADA 2019): Note: TDD of insulin is divided into a basal component (intermediate- or long-acting insulin) and nutritional and correctional components (regular insulin or rapid-acting insulins). Nutritional/correctional component: SubQ: 1 unit of insulin glulisine per 10 to 15 g of carbohydrate plus correctional insulin glulisine (as needed for hyperglycemia) administered every 4 hours or prior to each bolus feeding.

Patients with diabetes undergoing surgery and using continuous subcutaneous insulin infusion pump (ADA 2019): On the morning of surgery or procedure, give 60% to 80% of the usual dose of pump “basal” insulin (rapid-or short-acting insulins) dose.

Diabetic ketoacidosis (off-label use): IV: 0.1 unit/kg bolus, followed by a continuous infusion of 0.1 unit/kg/hour until blood glucose <250 mg/dL, then decrease to 0.05 unit/kg/hour until resolution of ketoacidosis. Discontinue IV infusion 2 hours after administration of subcutaneous insulin (Umpierrez 2009). Also, refer to institution-specific protocols where appropriate.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Pediatric

Insulin glulisine is a rapid-acting insulin analog which is normally administered SubQ as a premeal component of the insulin regimen or as a continuous SubQ infusion and should be used with an intermediate- or long-acting insulin. Insulin glulisine is equipotent to insulin regular, but has a more rapid onset and shorter duration of activity. In carefully controlled clinical settings with close medical supervision and monitoring of blood glucose and potassium, insulin glulisine may be administered IV in some situations. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision. See Insulin Regular for additional information.

General insulin dosing:

Type 1 diabetes mellitus: Children and Adolescents: Note: Multiple daily doses or continuous subcutaneous infusions guided by blood glucose monitoring are utilized. Combinations of insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined.

Initial dose: SubQ: 0.2-0.6 units/kg/day in divided doses. Conservative initial doses of 0.2-0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapidly acting insulin may be the only insulin formulation used initially.

Usual maintenance range: SubQ: 0.5-1 unit/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:

Nonobese: 0.4-0.6 units/kg/day

Obese: 0.8-1.2 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF/ISPAD, 2011)

Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.

Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion rate with preprogrammed premeal bolus doses which are patient controlled. When converting from multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than the equivalent of the total daily units of longer-acting insulin (eg, NPH); divide the total number of units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage may be used.

Dosing: Renal Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling; insulin requirements are reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in manufacturer's labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.

Use: Labeled Indications

Diabetes mellitus, types 1 and 2: Treatment of type 1 diabetes mellitus and type 2 diabetes mellitus to improve glycemic control

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Diabetic ketoacidosisLevel of Evidence [B]

Data from a prospective, randomized open label trial in a limited number of patients with diabetic ketoacidosis (DKA) comparing the use of IV insulin glulisine to a standard IV infusion protocol of regular insulin supports the use of insulin glulisine in the treatment of diabetic ketoacidosis ^Ref.

Hyperglycemia during critical illnessLevel of Evidence [A, G]

Data from two prospective, randomized, controlled trials in the ICU population supports the use of insulin in the management of hyperglycemia in this patient population ^Ref. However, more recent data suggest that intensive glucose control is not associated with reduced mortality or morbidity in the general critically ill adult patient or may even increase mortality and rate of severe hypoglycemia ^Ref.

The 2011 ACP clinical practice guideline for the management of glycemic control in hospitalized patients recommends against the use of intensive insulin therapy in non-SICU/MICU patients which includes patients suffering a myocardial infarction.

Based on the 2012 Society of Critical Care Medicine (SCCM) guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients, insulin glulisine is a recommended treatment option to manage hyperglycemia in critically ill patients who are clinically stable and have low insulin requirements. The 2012 SCCM guidelines suggest a glycemic goal range of 100 to 150 mg/dL, with absolute values <180 mg/dL ^Ref. The American Diabetes Association (ADA) recommends a target blood glucose of 140 to 180 mg/dL for the majority of critically ill patients ^Ref. The Surviving Sepsis Campaign guidelines recommend initiating insulin dosing in patients with severe sepsis when two consecutive blood glucose concentrations are >180 mg/dL and to target an upper blood glucose ≤180 mg/dL ^Ref.

Level of Evidence Definitions

Level of Evidence Scale

Class and Related Monographs

Insulin

Comparative Efficacy

• INSULIN GLULISINE

Clinical Practice Guidelines

Diabetes Mellitus:

American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE), “Consensus Statement on the Comprehensive Type 2 Diabetes Management Algorithm- 2019 Executive Summary”, January 2019

American Diabetes Association, “Standards of Medical Care in Diabetes - 2019,” January 2019

American Diabetes Association and the European Association for the Study of Diabetes Consensus Report, “Management of Hyperglycemia in Type 2 Diabetes, 2018,” December 2018

Diabetes Canada, “Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada,” 2018

Endocrine Society, “Diabetes Technology-Continuous Subcutaneous Insulin Infusion Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline,” 2016

Glycemic Control, Hospitalized Patients:

Society of Critical Care Medicine (SCCM), “Guidelines for the Use of an Insulin Infusion for the Management of Hyperglycemia in Critically Ill Patients,” December 2012.

Sepsis:

“Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016,” March 2017

Administration: IV

Use only if solution is clear and colorless; do not use if solution contains particulate matter or is colored. May be administered IV with close monitoring of blood glucose and serum potassium; appropriate medical supervision is required. Do not administer insulin mixtures intravenously.

IV infusions: To minimize insulin adsorption to plastic IV tubing: Although data is lacking regarding adsorption with insulin glulisine, insulin regular loss has been shown to occur by adsorption to plastic (ie, PVC, polyethylene, polyolefin, polypropylene) IV containers and tubing (Greenwood 2012; Hirsch 1977; Hirsch 1981; Rocchio 2013; Thompson 2012). Therefore, flush the IV tubing with a priming infusion of 20 mL from the insulin infusion, whenever a new IV tubing set is added to the insulin infusion container (SCCM [Jacobi 2012]; Thompson 2012).

Note: Also refer to institution-specific protocols where appropriate.

Because of insulin adsorption to plastic IV tubing or infusion bags, the actual amount of insulin being administered via IV infusion could be substantially less than the apparent amount. Therefore, adjustment of the IV infusion rate should be based on effect and not solely on the apparent insulin dose. The apparent dose may be used as a starting point for determining the subsequent SubQ dosing regimen (Moghissi 2009); however, the transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1 to 4 hours prior to the discontinuation of IV insulin to prevent hyperglycemia (Moghissi 2009).

Administration: Injectable Detail

pH: ~7.3

Administration: Subcutaneous

Use only if solution is clear and colorless; do not use if solution contains particulate matter or is colored. Insulin glulisine should be administered within 15 minutes before or within 20 minutes after starting a meal. Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, or abdomen; rotate injection sites within the same region to avoid lipodystrophy or localized cutaneous amyloidosis. Rotating from an injection site where lipodystrophy/cutaneous amyloidosis is present to an unaffected site may increase risk of hypoglycemia. Insulin glulisine from a vial may be mixed with insulin NPH only (do not mix with other types of insulin); insulin glulisine should be drawn into syringe first. Apidra SoloStar prefilled pens are designed to dial doses in 1-unit increments. Do not mix other insulin formulations with insulin glulisine contained in a cartridge or prefilled pen.

Continuous subcutaneous insulin infusion administration: Use only if solution is clear and colorless; do not use if solution contains particulate matter or is colored. Patients should be trained in the proper use of their external insulin pump and in intensive insulin therapy. Infusion sets, reservoirs, infusion set insertion sites, and the insulin in the reservoir should be changed every 48 hours or according to continuous subcutaneous insulin infusion device user manual (whichever is shorter); rotate infusion sites. Do not dilute or mix other insulin formulations with insulin glulisine that is to be used in an external insulin pump.

Administration: Pediatric

Parenteral: Do not use if solution is viscous or cloudy; use only if clear and colorless. May be administered IV with close monitoring of blood glucose and serum potassium; appropriate medical supervision is required. Do not administer insulin mixtures intravenously.

SubQ: Administration is usually made into the subcutaneous fat of the thighs, arms, buttocks, or abdomen, with sites rotated; cold injections should be avoided. May be mixed in the same syringe with NPH insulin. When mixing insulin glulisine with NPH insulin, glulisine should be drawn into the syringe first. Administer 15 minutes before meals or within 20 minutes after starting a meal.

Continuous SubQ insulin infusion (Insulin pump): Do not use if solution is viscous or cloudy; use only if clear and colorless. Patients should be trained in the proper use of their external insulin pump and in intensive insulin therapy. Infusion sets, reservoirs, and infusion set insertion sites should be changed every 48 hours; rotate infusion sites. Do not dilute or mix other insulin formulations with insulin glulisine that is to be used in an external insulin pump.

IV: Further dilute and administer using polyvinyl chloride infusion bags into a dedicated infusion line (the use of other bags and tubing has not been studied). Closely monitor blood glucose and serum potassium; appropriate medical supervision is required. Do not administer insulin mixtures intravenously.

To minimize insulin adsorption to IV tubing: Flush the IV tubing with a priming infusion of 20 mL from the insulin infusion, whenever a new IV tubing set is added to the insulin infusion container (Jacobi 2012; Thompson 2012). Also refer to institution-specific protocols where appropriate

Because of insulin adsorption to IV tubing or infusion bags, the actual amount of insulin being administered via IV infusion could be substantially less than the apparent amount. Therefore, adjustment of the IV infusion rate should be based on effect and not solely on the apparent insulin dose. The apparent dose may be used as a starting point for determining the subsequent SubQ dosing regimen (Moghissi 2009); however, the transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1 to 4 hours prior to the discontinuation of IV insulin to prevent hyperglycemia (Moghissi 2009).

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage/Stability

Unopened vials, cartridges, and prefilled pens may be stored under refrigeration between 2°C and 8°C (36°F to 46°F) until the expiration date or at room temperature for 28 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), vials may be stored under refrigeration or at room temperature ≤25°C (≤77°F); use within 28 days. Cartridges and prefilled pens that have been punctured (in use) should be stored at temperatures ≤25°C (≤77°F) and used within 28 days; do not freeze or refrigerate. When used for CSII, insulin glulisine contained within an external insulin pump reservoir should be replaced every 48 hours; discard if exposed to temperatures >37°C (>98.6°F).

For IV infusion: Stable in NS for 48 hours at room temperature.

Preparation for Administration: Adult

For IV infusion: May be diluted in NS to concentrations of 0.05-1 unit/mL.

Preparation for Administration: Pediatric

Parenteral:

SubQ: May be mixed in the same syringe with NPH insulin. When mixing insulin glulisine with NPH insulin, glulisine should be drawn into the syringe first.

IV: May be diluted in NS to concentrations of 0.05 to 1 unit/mL.

Compatibility

See Trissel’s IV Compatibility Database

Open Trissel's IV Compatibility

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower blood sugar in patients with high blood sugar (diabetes).

Frequently reported side effects of this drug

• Injection site irritation

• Nose irritation

• Throat irritation

• Common cold symptoms

• Flu-like symptoms

• Joint pain

• Headache

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Low blood sugar like dizziness, headache, fatigue, feeling weak, shaking, fast heartbeat, confusion, increased hunger, or sweating.

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.

• Blurred vision

• Chills

• Severe dizziness

• Passing out

• Mood changes

• Seizures

• Slurred speech

• Trouble focusing

• Shortness of breath

• Excessive weight gain

• Swelling of arms or legs

• Injection site thick skin, pits, or lumps

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

High alert medication:

Geriatric Patients: High-Risk Medication:

Other safety concerns:

Contraindications

Hypersensitivity to insulin glulisine or any component of the formulation; during episodes of hypoglycemia

Warnings/Precautions

Concerns related to adverse effects:

• Glycemic control: Hyperglycemia or hypoglycemia may result from changes in insulin strength, manufacturer, type, and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may change over time in the same patient; awareness may be less pronounced in those with long-standing diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.

• Hypersensitivity: Hypersensitivity reactions, including life-threatening reactions (anaphylaxis), can occur with insulin glulisine; discontinue, treat per standard of care, and monitor until signs and symptoms resolve.

• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium frequently with IV use and supplement potassium when necessary.

Disease-related concerns:

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones, may cause dose-related fluid retention and lead to or exacerbate heart failure (HF), particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of HF. If HF develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.

• Hepatic impairment: Use with caution in patients with hepatic impairment; may be at increased risk for hypoglycemia. Dosage requirements may be reduced and patients may require more frequent dose adjustments and blood glucose monitoring.

• Renal impairment: Use with caution in patients with renal impairment; may be at increased risk for hypoglycemia. Dosage requirements may be reduced and patients may require more frequent dose adjustments and blood glucose monitoring.

Special populations:

• Elderly: Use with caution in geriatric patients; may be more at risk for hypoglycemia. Consider conservative initial dosing, dose increments, and maintenance dose.

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia). A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2019).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Multiple dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

Other warnings/precautions:

• Continuous subcutaneous insulin infusion administration: May be administered via continuous subcutaneous insulin infusion; do not dilute or mix with other insulin formulations. Rule out external pump failure if unexplained hyperglycemia or ketosis occurs; temporary SubQ insulin administration may be required until the problem is identified and corrected.

• IV administration: Insulin glulisine may be administered IV in selected clinical situations to control hyperglycemia; close monitoring of blood glucose and serum potassium as well as medical supervision is required.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

Intensive glucose control (HbA_1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA_1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. In patients with advanced microvascular complications and/or a life expectancy <5 years, a target HbA_1c of 8% to 9% is reasonable. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.

Pregnancy Considerations

Based on available information, maternal use of insulin glulisine is not associated with an increased risk of adverse pregnancy outcomes (Doder 2015).

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major birth defects, stillbirth, and macrosomia. To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA_1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2020; Blumer 2013).

Due to pregnancy-induced physiologic changes, insulin requirements tend to increase as pregnancy progresses, requiring frequent monitoring and dosage adjustments. Following delivery, insulin requirements decrease rapidly (ACOG 201 2018; ADA 2020).

Insulin is the preferred treatment of type 1 and type 2 diabetes mellitus in pregnancy, as well as gestational diabetes mellitus when pharmacologic therapy is needed (ACOG 190 2018; ACOG 201 2018; ADA 2020). Agents other than insulin glulisine are currently recommended to treat diabetes mellitus in pregnancy (ACOG 190 2018; ACOG 201 2018; Blumer 2013).

Breast-Feeding Considerations

Both exogenous and endogenous insulin are present in breast milk (study not conducted with this preparation) (Whitmore 2012).

Adverse events have not been reported in breastfed infants following maternal use of insulin glulisine.

Breastfeeding is encouraged for all females, including those with type 1, type 2, or gestational diabetes mellitus (ACOG 201 2018; ADA 2020; Blumer 2013). A small snack before breastfeeding may help decrease the risk of hypoglycemia in females with pregestational diabetes (ACOG 201 2018; Reader 2004). According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Lexicomp Pregnancy & Lactation, In-Depth

• Insulin Glulisine

Briggs' Drugs in Pregnancy & Lactation

• Insulin Glulisine

Adverse Reactions

>10%:

Endocrine & metabolic: Severe hypoglycemia (1% to 8%; children and adolescents, type 1 diabetes: 16%)

Respiratory: Nasopharyngitis (8% to 11%), upper respiratory tract infection (7% to 11%)

1% to 10%:

Cardiovascular: Peripheral edema (8%; adults, type 2 diabetes), hypertension (4%; adults, type 2 diabetes)

Central nervous system: Headache (7%; children and adolescents, type 1 diabetes), hypoglycemic seizure (6%; children and adolescents, type 1 diabetes)

Endocrine & metabolic: Hypoglycemia (7%; adults, type 1 diabetes)

Hypersensitivity: Hypersensitivity reaction (4%)

Infection: Influenza (4% to 6%)

Local: Infusion site reaction (10%)

Neuromuscular & skeletal: Arthralgia (6%; adults, type 2 diabetes)

Frequency not defined:

Dermatologic: Pruritus, skin rash

Endocrine & metabolic: Hypokalemia, weight gain

Hypersensitivity: Anaphylaxis

Immunologic: Antibody development (no effect on drug efficacy)

Local: Erythema at injection site, hypertrophy at injection site, itching at injection site, lipoatrophy at injection site, swelling at injection site

<1%, postmarketing, and/or case reports: Catheter complication

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

• Insulin Preparation Allergy

Toxicology

• Insulins

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Exceptions: Danazol. Risk C: Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Exceptions: Liraglutide. Risk D: Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Risk D: Consider therapy modification

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Risk X: Avoid combination

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Risk D: Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Risk D: Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Risk D: Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Risk X: Avoid combination

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Monitoring Parameters

Critically ill patients receiving insulin infusion: Blood glucose every 1 to 2 hours. Note: Every 4 hour blood glucose monitoring is not recommended unless a low hypoglycemia rate is demonstrated with the insulin protocol used. Arterial or venous whole blood sampling is recommended for patients in shock, on vasopressor therapy, or with severe edema, and when on a prolonged insulin infusion (SCCM [Jacobi 2012]).

Diabetes mellitus: Plasma glucose (typically before meals and snacks and at bedtime; occasionally additional monitoring may be required), electrolytes, HbA_1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2019]), renal function, hepatic function, weight

Gestational diabetes mellitus: Blood glucose 4 times daily (1 fasting and 3 postprandial) until well controlled, then as appropriate (ACOG 190 2018).

IV administration: Close monitoring of blood glucose and serum potassium

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2019):

HbA_1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA_1c goal may be targeted based on patient-specific characteristics)

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Peak postprandial capillary blood glucose: <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics)

Older adults (≥65 years) (ADA 2019):

HbA_1c: <7.5% (healthy); <8% (complex/intermediate health); <8.5% (very complex/poor health) (individualization may be appropriate based on patient and caregiver preferences)

Preprandial capillary blood glucose: 90 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health)

Bedtime capillary blood glucose: 90 to 150 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health)

Pregnant patients:

HbA_1c: Pregestational diabetes (type 1 or type 2) (ADA 2019):

Preconception (patients planning for pregnancy): <6.5%

During pregnancy <6% (if can be achieved without significant hypoglycemia) or <7% if needed to prevent hypoglycemia

Capillary blood glucose: Pregestational diabetes mellitus (type 1 or type 2) (ADA 2019) or gestational diabetes mellitus (ACOG 190 2018) (less stringent targets may be appropriate if goals cannot be achieved without causing significant hypoglycemia):

Fasting: <95 mg/dL

Postprandial: <140 mg/dL (at 1 hour) or <120 mg/dL (at 2 hours)

Pediatric (all age groups) patients with type 1 diabetes (ADA 2019):

HbA_1c: <7.5% (individualization may be appropriate based on patient-specific characteristics; <7% is reasonable if it can be achieved without excessive hypoglycemia)

Preprandial capillary blood glucose: 90 to 130 mg/dL

Bedtime and overnight capillary blood glucose: 90 to 150 mg/dL

Hospitalized adult patients (ADA 2019): Target glucose range: 140 to 180 mg/dL (majority of critically ill and noncritically ill patients; <140 mg/dL may be appropriate for selected patients, if it can be achieved without excessive hypoglycemia). Initiate insulin therapy for persistent hyperglycemia at ≥180 mg/dL

Perioperative care in adult patients (ADA 2019): Target glucose range during perioperative period: Consider targeting 80 to 180 mg/dL

Classification of hypoglycemia (ADA 2019):

Level 1: ≥54 to ≤70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment

Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance

Advanced Practitioners Physical Assessment/Monitoring

Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements.

Nursing Physical Assessment/Monitoring

Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Apidra: 100 units/mL (10 mL) [contains metacresol]

Solution Pen-injector, Subcutaneous:

Apidra SoloStar: 100 units/mL (3 mL) [contains metacresol]

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Subcutaneous:

Apidra: 100 units/mL (10 mL) [contains metacresol]

Solution Cartridge, Subcutaneous:

Apidra: 100 units/mL (3 mL) [contains metacresol]

Apidra Optiset: 100 units/mL ([DSC]) [contains metacresol]

Solution Pen-injector, Subcutaneous:

Apidra SoloStar: 100 units/mL (3 mL) [contains metacresol]

Anatomic Therapeutic Chemical (ATC) Classification

• A10AB06

Generic Available (US)

No

Pricing: US

Solution (Apidra Injection)

100 units/mL (per mL): $34.07

Solution Pen-injector (Apidra SoloStar Subcutaneous)

100 units/mL (per mL): $43.88

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.

Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Insulin glulisine differs from human insulin by containing a lysine and glutamic acid at positions B3 and B29, respectively, in comparison to the asparagine and lysine found at B3 and B29 in human insulin. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin glulisine is a rapid-acting insulin analog.

Pharmacodynamics/Kinetics

Note: Onset and duration of hypoglycemic effects depend upon the route of administration (absorption and onset of action are more rapid after deeper IM injections than after SubQ), site of injection (onset and duration are progressively slower with SubQ injection into the abdomen, arm, buttock, or thigh respectively), volume and concentration of injection, and the preparation administered. Rate of absorption, onset, and duration of activity may be affected by exercise, presence of lipodystrophy, local blood supply, and/or temperature.

Onset of action: 0.2-0.5 hours

Peak effect: 1.6-2.8 hours

Duration: 3-4 hours

Distribution: IV: 13 L

Bioavailability: SubQ: ~70%

Half-life elimination:

IV: 13 minutes

SubQ: 42 minutes

Time to peak, plasma: 60 minutes (range: 40-120 minutes)

Excretion: Urine

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Insulin clearance may be reduced in patients with impaired renal function.

Obesity: T_max occurs faster and C_max is greater with insulin glulisine compared with regular human insulin in obese patients.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: In general, morning appointments are advisable in patients with diabetes since endogenous cortisol levels are typically higher at this time; because cortisol increases blood sugar levels, the risk of hypoglycemia is less. It is important to confirm that the patient has eaten normally prior to the appointment and has taken all scheduled medications. If a procedure is planned with the expectation that the patient will alter normal eating habits ahead of time (eg, conscious sedation), diabetes medication dose may need to be modified in consultation with the patient’s physician. Patients with well-controlled diabetes can usually be managed conventionally for most surgical procedures. Although patients with diabetes usually recognize signs and symptoms of hypoglycemia and self-intervene before changes in or loss of consciousness occurs, they may not. Staff should be trained to recognize the signs (eg, unusual behavior or profuse sweating in patients who have diabetes) and treat patients who have hypoglycemia; a glucometer should be used to test patient blood glucose levels. Every dental office should have a protocol for managing hypoglycemia in conscious and unconscious patients. Having snack foods or oral glucose tablets or gels available, especially in practices where a large number of surgical procedures are performed, is also prudent (American Diabetes Association 2017).

Effects on Bleeding

No information available to require special precautions

Related Information

• Beers Criteria 2019: Potentially Inappropriate Medication Use in Older Adults ≥65 Years of Age
• Insulin Products

Pharmacotherapy Pearls

Split-mixed or basal-bolus regimens: Combination regimens which optimize differences in the onset and duration of different insulin products are commonly used to approximate physiologic secretion. In split-mixed regimens, an intermediate-acting insulin (eg, NPH insulin) is administered once or twice daily and supplemented by short-acting (regular) or rapid-acting (eg, glulisine, aspart, or lispro) insulin. Blood glucose measurements are completed several times daily. Dosages are adjusted emphasizing the individual component of the regimen which most directly influences the blood sugar in question (either the intermediate-acting component or the shorter-acting component). Fixed-ratio formulations (eg, 70/30 mix) may be used as twice daily injections in this scenario; however, the ability to titrate the dosage of an individual component is limited. An example of a “split-mixed” regimen would be 21 units of NPH plus 9 units of glulisine in the morning and an evening meal dose consisting of 14 units of NPH plus 6 units of glulisine.

Basal-bolus regimens are designed to closely mimic physiologic secretion. These regimens employ a long-acting insulin (eg, degludec, detemir, glargine) to simulate basal insulin secretion. The basal component is frequently administered at bedtime or in the early morning. This is supplemented by multiple daily injections of rapid-acting products immediately prior to a meal, which provides insulin at the time when nutrients are absorbed. An example of a basal-bolus regimen would be 30 units of glargine at bedtime and 12 units of glulisine prior to each meal.

Estimation of the effect per unit: A “Rule of 1500” has been frequently used as a means to estimate the change in blood sugar relative to each unit of insulin administered. In fact, the recommended values used in these calculations may vary from 1500 to 2200 (a value of 1500 is generally recommended for regular insulin while 1800 is recommended for "rapid-acting insulins"). The higher values lead to more conservative estimates of the effect per unit of insulin, and therefore lead to more cautious adjustments. The effect per unit of insulin is approximated by dividing the selected numerical value (eg, 1500 to 2200) by the number of units/day received by the patient. This may be used as a crude approximation of the patient's insulin sensitivity as adjustments to individual components of the regimen are made. Each additional unit of insulin added to the corresponding insulin dose may be expected to lower the blood glucose by this amount.

To illustrate, in the “basal-bolus” regimen example presented above, the rule of 1800 would indicate an expected change of 27 mg/dL per unit of glulisine (the total daily insulin dose is 66 units; using the formula: 1800/66 = 27). A patient may be instructed to add additional insulin if the preprandial glucose is >125 mg/dL. For a prelunch glucose of 195 mg/dL, this would mean the patient would administer the scheduled 12 units of glulisine along with an additional “correctional” 3 units for a total of 15 units of glulisine prior to the meal. If correctional doses are required on a consistent basis, an adjustment of the patients diet and/or scheduled insulin dose may be necessary.

Index Terms

Glulisine Insulin

FDA Approval Date

April 16, 2004

References

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Brand Names: International

Apidra (AE, AR, AT, AU, BB, BE, BG, BH, BR, BS, CH, CL, CO, CR, CY, CZ, DE, DK, DO, EC, EE, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, ID, IE, IL, IN, IS, IT, JM, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MX, MY, NI, NL, NO, NZ, PA, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TT, TW, UA, UY, VN); Shorant (CR, DO, GT, HN, MX, NI, PA, SV)

Last Updated 2/20/20