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Insulin Glulisine

Medically reviewed by Drugs.com. Last updated on Jun 7, 2020.

Pronunciation

(IN soo lin gloo LIS een)

Index Terms

  • Glulisine Insulin

Dosage Forms

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]

Brand Names: U.S.

  • Apidra
  • Apidra SoloStar

Pharmacologic Category

  • Insulin, Rapid-Acting

Pharmacology

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.

Distribution

IV: 13 L

Excretion

Urine

Onset of Action

0.2-0.5 hours; Peak effect: 1.6-2.8 hours

Time to Peak

Plasma: 60 minutes (range: 40-120 minutes)

Duration of Action

3-4 hours

Half-Life Elimination

IV: 13 minutes

SubQ: 42 minutes

Special Populations: Renal Function Impairment

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

Special Populations Note

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

Use: Labeled Indications

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

Off Label Uses

Diabetic ketoacidosis

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 [Umpierrez 2009].

Hyperglycemia during critical illness

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 [Van den Berghe 2001], [Van den Berghe 2006]. 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 [NICE-SUGAR Study Investigators 2009], [ Wiener 2008].

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 [Jacobi 2012]. The American Diabetes Association (ADA) recommends a target blood glucose of 140 to 180 mg/dL for the majority of critically ill patients [ADA 2020]. 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 [Rhodes 2017].

Contraindications

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

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, treatment: 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 2020).

Usual total daily dose maintenance range: 0.4 to 1 units/kg/day in divided doses (ADA 2020).

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 2020).

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 2020).

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 2020]; ADA 2020): 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 HbA1c 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%.

HbA1c 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 2020): 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 an insulin pump (ADA 2020): SubQ: For short procedures (eg, <2 hours), continue the usual pump “basal” insulin infusion rate, with or without a temporary 20% to 40% rate reduction, on the morning of the procedure. For long and complex procedures, consider transitioning from the insulin pump to an IV regular insulin infusion perioperatively (ADA 2020; Leung 2017).

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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Insulin glulisine is a rapid-acting insulin analog. Insulin doses should be individualized based on patient needs; adjustments may be necessary with changes in physical activity, meal patterns, acute illness, or with changes in renal or hepatic function. Insulin requirements vary dramatically between patients and dictates frequent monitoring and close medical supervision. Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.

Type 1 diabetes mellitus: Children and Adolescents: Note: Insulin glulisine is generally used concomitantly with intermediate- or long-acting insulin (ie, multiple daily injection regimen) or in a continuous subcutaneous infusion pump. The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined.

General insulin dosing:

Initial total daily insulin: SubQ: Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2020); usual range: 0.4 to 1 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2020; Silverstein 2005); lower doses (0.25 units/kg/day) may be used, especially in young children, to avoid potential hypoglycemia (Beck 2015); higher doses may be necessary for some patients (eg, obese, concomitant steroids, puberty, sedentary lifestyle, following diabetic ketoacidosis presentation) (AACE/ACE [Handelsman 2015]; ADA 2020; Silverstein 2005).

Usual total daily maintenance range: SubQ: Doses must be individualized; however, an estimate can be determined based on phase of diabetes and level of maturity (ISPAD [Danne 2018]; ISPAD [Sundberg 2017]).

Partial remission phase (Honeymoon phase): <0.5 units/kg/day.

Prepubertal children (not in partial remission):

Infants ≥6 months and Children ≤6 years: 0.4 to 0.8 units/kg/day.

Children ≥7 years: 0.7 to 1 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.

Division of daily insulin requirement (multiple daily injections):

Basal insulin: Generally, ~30% to 50% of the total daily insulin is given as basal insulin (intermediate- or long-acting) in 1 to 2 daily injections (AACE/ACE [Handelsman 2015]; ADA 2020; ISPAD [Danne 2018]; Peters 2013).

Prandial insulin: The remaining portion of the total daily dose is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, aspart, glulisine, lispro) or short-acting (regular). In most type 1 patients, the use of a rapid-acting insulin analog is preferred over regular insulin to reduce hypoglycemia risk (AACE/ACE [Handelsman 2015]; ADA 2020; ADA [Chiang 2014]; ISPAD [Danne 2018]).

Dosage titration: Treatment and monitoring regimens must be individualized to maintain premeal and bedtime glucose in target range; titrate dose to achieve glucose control and avoid hypoglycemia. 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.

Surgical patients (ISPAD [Jefferies 2018]): Note: Diabetic patients should be scheduled as the first case of the day.

Minor surgeries:

Morning procedure: Omit rapid-acting insulin (eg, aspart, glulisine, lispro) until after surgery and patient is able to eat unless it is needed to correct significant hyperglycemia and/or significant ketone (>0.1 mmol/mol) production is present.

Afternoon procedure: If allowed to eat breakfast, administer the usual dose of rapid-acting insulin (eg, aspart, glulisine, lispro) with breakfast.

Postprocedure: Once normal oral intake is achieved, resume usual insulin regimen; monitor closely; insulin requirement may be higher due to changes related to surgery (ie, postoperative stress, medication changes, inactivity).

Major surgeries:

Evening prior to surgery: Administer the usual evening and/or bedtime insulin(s); patients on continuous subcutaneous insulin infusion (CSII) may continue normal insulin basal rates overnight; if there is a concern for hypoglycemia, basal rate may be reduced by 20% at ~3 am.

Morning of surgery: Omit morning insulin (short- and long-acting) and start IV insulin (regular) infusion and IV dextrose at least 2 hours prior to surgery; patients on CSII should discontinue CSII when IV insulin infusion is started.

Postprocedure: Once normal oral intake is achieved, resume usual insulin regimen; monitor closely; insulin requirement may be higher due to changes related to surgery (ie, postoperative stress, medication changes, inactivity).

Type 2 diabetes mellitus: Children ≥10 years and Adolescents: SubQ: The goal of therapy is to achieve an HbA1c <7% as quickly as possible using the safe titration of medications. Initial therapy in metabolically unstable patients (eg, plasma glucose ≥250 mg/dL, HbA1c >8.5%, symptoms excluding acidosis) may include once-daily intermediate-acting insulin or basal insulin in combination with lifestyle changes and metformin. In patients who fail to achieve glycemic goals with metformin and basal insulin, may consider initiating prandial insulin (regular insulin or rapid-acting insulin) and titrate to achieve goals. Once initial goal reached, insulin should be slowly tapered over 2 to 6 weeks by decreasing the insulin dose by 10% to 30% every few days and the patient transitioned to lowest effective doses or metformin monotherapy if able (AAP [Copeland 2013]; ADA 2020; ADA [Arslanian 2018]; ISPAD [Zeitler 2018]). Note: Patients who are ketotic or present with ketoacidosis require aggressive management.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Reconstitution

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

Administration

Use only if solution is clear and colorless; do not use if solution contains particulate matter or is colored.

SubQ administration: 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: 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.

IV administration: 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).

Dietary Considerations

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

Storage

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.

Drug Interactions

Alpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Consider therapy modification

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

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

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

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. 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. Consider therapy modification

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

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. 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. Consider therapy modification

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

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

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

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

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

Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: Consider reducing the liraglutide dose if coadministered with insulin. Prescribing information for the Saxenda brand of liraglutide recommends a dose decrease of 50%. Monitor blood glucose for hypoglycemia. Consider therapy modification

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

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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 for signs and symptoms of hypoglycemia. Consider therapy modification

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

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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, consider insulin dose reductions to avoid hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure, and consider pioglitazone dose reduction or discontinuation if heart failure occurs 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. Consider therapy modification

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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. 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. Avoid combination

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

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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. Consider therapy modification

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

Adverse Reactions

>10%:

Endocrine & metabolic: Severe hypoglycemia (7% to 16%; type 1 diabetes)

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)

Hypersensitivity: Hypersensitivity reaction (4%)

Infection: Influenza (4% to 6%)

Local: Infusion site reaction (10%)

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

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

Frequency not defined:

Endocrine & metabolic: 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: Amyloidosis (cutaneous at injection site), catheter complication

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:

• Bariatric surgery:

– Type 2 diabetes, hypoglycemia: Closely monitor insulin dose requirement throughout active weight loss with a goal of eliminating antidiabetic therapy or transitioning to agents without hypoglycemic potential; hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band may occur (Mechanick 2013). Insulin secretion and sensitivity may be partially or completely restored after these procedures (Korner 2009; Peterli 2012). Rates and timing of type 2 diabetes improvement and resolution vary widely by patient. Insulin dose reduction of ≥75% has been suggested after gastric bypass for patients without severe beta-cell failure (fasting c-peptide <0.3 nmol/L) (Cruijsen 2014). Avoid the use of bolus insulin injections or dose conservatively with close clinical monitoring in the early phases after surgery.

– Weight gain: Insulin therapy is preferred if antidiabetic therapy is required during the perioperative period (Mechanick 2019). Evaluate risk versus benefit of long-term post-operative use and consider alternative therapy due to potential for insulin-induced weight gain (Apovian 2015).

• 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 2020).

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.

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, HbA1c (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 2020]), 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

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 HbA1c 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).

Patient Education

What is this drug used for?

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

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Injection site irritation

• Nose irritation

• Throat irritation

• Common cold symptoms

• Flu-like symptoms

• Joint pain

• Headache

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.