Insulin Lispro + Insulin Lispro Protamine

Pharmacologic Category

Insulin, Combination

Dosing: Adult

Note: Lispro protamine is an intermediate-acting insulin and lispro is a rapid-acting insulin administered by SubQ injection. Insulin lispro protamine and insulin lispro combination products are approximately equipotent to insulin NPH and insulin regular combination products with a similar duration of activity but a more rapid onset. With combination insulin products, the proportion of rapid-acting to long-acting insulin is fixed; basal vs prandial dose adjustments cannot be made. Because of variability in the peak effect and individual patient variability in activities, meals, etc, it may be more difficult to achieve complete glycemic control using fixed combinations of insulins.

Diabetes mellitus, type 1: SubQ:

General insulin dosing:

Note: Use of premixed insulin is not generally recommended in type 1 diabetes. Most patients should be treated with multiple daily injections of prandial and basal insulin or continuous subcutaneous insulin infusion (CSII) (ADA 2019; Peters 2013). The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

Initial TDD: ~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 TDD maintenance range: 0.4 to 1 units/kg/day in divided doses (ADA 2019).

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Note: If using insulin lispro protamine and insulin lispro combination, the TDD is typically divided into 2 doses. Given the fixed proportion of individual components in premixed insulin combination products, independent adjustment of the basal or prandial component is not possible. Therefore, use of premixed insulins should be reserved for patients unwilling to take more than two daily doses of insulin and unable to mix individual insulins. In these patients, consistent carbohydrate intake at each meal is essential (Peters 2013).

Diabetes mellitus, type 2: SubQ: Note: Initiation of premixed insulin is an option if adequate glycemic control has not been achieved with other injectable therapy including a GLP-1 receptor agonist and/or basal insulin (± prandial insulin) (ADA 2019).

Initial: If insulin naive, administer 0.3 units/kg/day or 10 to 12 units/day in 2 or 3 divided doses or if converting from other insulin therapy, administer the current total daily insulin dose in 2 or 3 divided doses (dose may require adjustment based on individual patient needs) (ADA 2019).

Dosage adjustment (ADA 2019): Individualize dose adjustment based on type of biphasic insulin used; adjustment may be more complex with three times daily regimen. Risk of hypoglycemia is greater given the fixed proportion of individual components.

In patients who develop hypoglycemia (without clear reason), dosage reductions of 10% to 20% have been recommended for basal and prandial insulins (as individual components); in cases of severe hypoglycemia (requiring assistance from another person or blood glucose <40 mg/dL) dosage reductions of 20% to 40% have been recommended (AACE/ACE [Garber 2019]; ADA 2019).

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

Lispro protamine is an intermediate-acting insulin and lispro is a rapid-acting insulin; the combination product is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of combination insulin products. Insulin lispro protamine and insulin lispro combination products are approximately equipotent to insulin NPH and insulin regular combination products with a similar duration of activity but a more rapid onset. Because of variability in the peak effect and individual patient variability in activities, meals, etc., it may be more difficult to achieve complete glycemic control using fixed combinations of insulins; frequent monitoring and close medical supervision may be necessary. Premixed insulins are not recommended for routine use in pediatric patients; the proportion of rapid-acting to long-acting insulin is fixed; basal vs prandial dose adjustments cannot be made; premixed insulins may be useful when adherence is an issue (AACE/ACE [Handelsman 2015]; Beck 2015; ISPAD [Danne 2018]). Insulin regimens vary widely by region, practice, and institution; consult institution-specific guidelines.

Type 1 diabetes mellitus: Limited data available: Children and Adolescents: Note: Fixed ratio insulins (such as insulin lispro protamine and insulin lispro combination) are typically administered as 2 daily doses prior to meals (each dose is intended to cover 2 meals or a meal and a snack).

General insulin dosing: The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined. Premixed insulin is not recommended for routine use in pediatric patients; may be useful when adherence is an issue (Beck 2015; ISPAD [Danne 2018]).

Initial total daily insulin: SubQ: Initial: 0.4 to 0.5 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2018); usual range: 0.4 to 1 units/kg/day in divided doses (AACE/ACE [Handelsman 2015]; ADA 2018; 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 2018).

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

Dose 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. With combination insulin products, the proportion of rapid-acting to long-acting insulin is fixed; basal vs prandial dose adjustments cannot be made.

Type 2 diabetes mellitus: Limited data available: Children ≥10 years and Adolescents: SubQ: The goal of therapy is to achieve an HbA_1c <7% as quickly as possible using the safe titration of medications. Initial therapy in metabolically unstable patients (eg, plasma glucose ≥250 mg/dL, HbA_1c >9% and 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 2018; ISPAD [Zeitler 2018]). Insulin lispro protamine and insulin lispro combination product is not intended for initial therapy; basal insulin requirements should be established first to direct dosing of combination insulin products. Note: Patients who are ketotic or present with ketoacidosis require aggressive management as indicated.

Dosing: Renal 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.

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

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

Administration: Subcutaneous

Insulin lispro protamine and insulin lispro combination product is administered by SubQ injection, typically in 2 divided doses/day with each dose intended to cover 2 meals or a meal and a snack; administer within 15 minutes before a meal. Administer into the thigh, upper arm, buttocks, or abdomen; absorption rates vary amongst injection sites; be consistent with area used while rotating injection sites within the same region to reduce the risk of 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.

In order to properly resuspend the insulin, vials should be carefully shaken or rolled several times and prefilled pens should be rolled between the palms ten times and inverted 180° ten times. Properly resuspended insulin should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, if the insulin remains clear after adequate mixing, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided.

Do not administer IM or IV, or in an insulin pump. Do not dilute or mix with any other insulin formulation or solution.

For prefilled pens, prime the needle before each injection with 2 units of insulin. Once injected, hold the needle in the skin for a count of 5 after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered. Humalog 75/25 and 50/50 Flexpens are designed to dial doses in 1-unit increments.

Administration: Pediatric

SubQ: For subcutaneous administration into the thighs, arms, buttocks, or abdomen; Not for IM or IV administration or use in an insulin infusion pump. Rotate injection sites within the same region to reduce the risk of lipodystrophy. Properly resuspended insulin should look uniformly cloudy or milky; do not use if any white insulin substance remains at the bottom of the container, if any clumps are present, if the insulin remains clear after adequate mixing, or if white particles are stuck to the bottom or wall of the container. Cold injections should be avoided. Administer within 15 minutes before a meal (breakfast and supper). Do not mix or dilute with other insulins.

Vials: In order to properly resuspend the insulin, vials should be gently rolled between the palms at least 10 times and carefully inverted at least 10 times.

Humalog KwikPen: In order to properly resuspend the insulin, the pen should be gently rolled between the palms at least 10 times and inverted 180° at least 10 times. Prime the needle before each injection with 2 units of insulin; see manufacturer's labeling for specific procedure. Once primed, set dial to the appropriate dose, insert needle into clean skin, and activate device. Once injected, hold the needle in the skin for a count of 5 keeping the button depressed the entire time and then remove the needle. Check to see if there is a 0 in the dose window, which indicates that the full dose has been administered. If there is no 0 in the dose window, insert needle into the skin and finish injection. Do not redial.

Dietary Considerations

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

Storage/Stability

Unopened vials 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 <30°C (<86°F) for 10 days (prefilled pens) or 28 days (vials); do not freeze; keep away from heat and sunlight. Once punctured (in use), vials may be stored under refrigeration or at room temperature <30°C (<86°F); use within 28 days. Prefilled pens that have been punctured (in use) should be stored at room temperature <30°C (<86°F) and used within 10 days; do not freeze or refrigerate.

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).

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

• Severe injection site irritation

• Vision changes

• Severe dizziness

• Passing out

• Mood changes

• Seizures

• Slurred speech

• Shortness of breath

• Excessive weight gain

• Swelling of arms of legs

• Fatigue

• Change in skin to thick or thin at injection site

• 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:

Other safety concerns:

Contraindications

Hypersensitivity to any component of the formulation; during episodes of hypoglycemia

Warnings/Precautions

Concerns related to adverse effects:

• Glycemic control: Hyper- 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: Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur. If hypersensitivity reactions occur, discontinue therapy, treat the patient with supportive 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 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 at least 75% has been suggested after gastric bypass for patients without severe β-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: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

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

• Hepatic impairment: Use with caution in patients with hepatic impairment. Dosage requirements may be reduced.

• Renal impairment: Use with caution in patients with renal impairment. Dosage requirements may be reduced.

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.

Special populations:

• 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).

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:

• Administration: Insulin lispro protamine and insulin lispro premixed combination products are NOT intended for IV or IM administration or administration in an insulin infusion pump.

• Appropriate use: Not recommended for treatment of diabetic ketoacidosis (Kitabchi 2009).

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

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

Insulin lispro has not been shown to cross the placenta at standard clinical doses (Boskovic 2003; Holcberg 2004; Jovanovic 1999).

Refer to Insulin Lispro monograph for additional information.

Breast-Feeding Considerations

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

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.

Refer to Insulin Lispro monograph for additional information.

Lexicomp Pregnancy & Lactation, In-Depth

• Insulin Lispro

Briggs' Drugs in Pregnancy & Lactation

• Insulin Lispro

Adverse Reactions

Also see insulin lispro for additional reactions.

Dermatologic: Pruritus, skin rash

Endocrine & metabolic: Hypoglycemia, lipodystrophy

Hypersensitivity: Hypersensitivity reaction

Local: Injection site reaction, lipotrophy at injection site

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

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 (one fasting and three postprandial) until well controlled, then as appropriate (ACOG 190 2018)

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 of age) (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):

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

Obtain serum glucose, electrolytes, HbA_1c (at least twice yearly in patients meeting goals and quarterly in patient not meeting goals), weight, renal function tests, and liver function tests. Assess for signs of hypoglycemia. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements. Refer to dietician and/or diabetes self-management education.

Nursing Physical Assessment/Monitoring

Check ordered labs and report abnormalities. Monitor for hypoglycemia at regular intervals during therapy. Teach patient proper use, including appropriate injection technique and syringe/needle disposal, and monitoring requirements. Educate and instruct patient to report signs of hypoglycemia (dizziness, headache, fatigue, weakness, shaking, fast heartbeat, confusion, hunger, or sweating) or hypokalemia (muscle pain or weakness, muscle cramps, or an abnormal heartbeat). May need referral to dietician and/or diabetes self-management education.

Dosage Forms: US

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

Suspension, Subcutaneous:

HumaLOG Mix 50/50: Insulin lispro protamine suspension 50% [intermediate acting] and insulin lispro solution 50% [rapid acting]: 100 units/mL (10 mL)

HumaLOG Mix 75/25: Insulin lispro protamine suspension 75% [intermediate acting] and insulin lispro solution 25% [rapid acting]: 100 units/mL (10 mL)

Suspension Pen-injector, Subcutaneous:

HumaLOG Mix 50/50 KwikPen: Insulin lispro protamine suspension 50% [intermediate acting] and insulin lispro solution 50% [rapid acting]: 100 units/mL (3 mL)

HumaLOG Mix 75/25 KwikPen: Insulin lispro protamine suspension 75% [intermediate acting] and insulin lispro solution 25% [rapid acting]: 100 units/mL (3 mL)

Anatomic Therapeutic Chemical (ATC) Classification

• A10AD04

Generic Available (US)

No

Pricing: US

Suspension (HumaLOG Mix 50/50 Subcutaneous)

(50-50) 100 units/mL (per mL): $34.16

Suspension (HumaLOG Mix 75/25 Subcutaneous)

(75-25) 100 units/mL (per mL): $34.16

Suspension Pen-injector (HumaLOG Mix 50/50 KwikPen Subcutaneous)

(50-50) 100 units/mL (per mL): $42.43

Suspension Pen-injector (HumaLOG Mix 75/25 KwikPen Subcutaneous)

(75-25) 100 units/mL (per mL): $42.43

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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 lispro differs from human insulin by containing a lysine and proline at positions B28 and B29, respectively, in comparison to the proline and lysine found at B28 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 lispro protamine and insulin lispro is an intermediate-acting combination product with a more rapid onset and similar duration of action as compared to that of insulin NPH and insulin regular combination products.

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: 0.25 to 0.5 hours

Peak effect:

Humalog Mix 50/50: 0.8 to 4.8 hours

Humalog Mix 75/25: 1 to 6.5 hours

Duration: 14 to 24 hours

Time to peak, plasma:

Humalog Mix 50/50: 0.75 to 13.5 hours

Humalog Mix 75/25: 0.5 to 4 hours

Excretion: Urine

Pharmacodynamics/Kinetics: Additional Considerations

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

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

• Insulin Lispro
• Insulin Products

Index Terms

Humalog Mix; Humalog Mix 75/25; Insulin Lispro and Insulin Lispro Protamine; Lispro Insulin and Insulin Lispro Protamine

References

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Humalog [prescribing information]. Indianapolis, IN: Eli Lilly and Company; March 2013.

Humalog (insulin lispro protamine and insulin lispro) [product monograph]. Scarborough, Ontario, Canada: Eli Lilly Canada; November 2017.

Humalog KwikPen (insulin lispro protamine and insulin lispro) [product monograph]. Scarborough, Ontario, Canada: Eli Lilly Canada; November 2017.

Humalog Mix 25 (insulin lispro protamine and insulin lispro) [product monograph]. Scarborough, Ontario, Canada: Eli Lilly Canada; November 2017.

Humalog Mix 50 (insulin lispro protamine and insulin lispro) [product monograph]. Scarborough, Ontario, Canada: Eli Lilly Canada; November 2017.

Humalog Mix 50/50 (50% insulin lispro protamine suspension and 50% insulin lispro injection [rDNA origin] solution) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2019.

Humalog Mix 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection [rDNA origin] suspension) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; November 2019.

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Brand Names: International

Humalog 25 (CN); Humalog 50/50 (VN); Humalog 75/25 (VN); Humalog Mix (AT, BE, CH, CZ, DE, DK, EE, ES, FR, GB, GR, HR, HU, IE, IL, IS, JO, LK, LT, LU, LV, MT, NO, PL, PT, RO, RU, SE, SI, SK, TR, TW); Humalog Mix 25 (AE, AU, BB, BH, BM, BR, BS, BZ, CL, CO, CR, CY, DO, GT, GY, HK, HN, IL, JM, KR, KW, LB, MX, MY, NI, NL, NZ, PA, PE, PH, PR, QA, SA, SG, SR, SV, TH, TT, VE); Humalog Mix 50 (AE, AU, BB, BH, CY, IL, KW, LB, MY, QA, SA, TH); Humalog NPL (AE, BH, IL, KW); Humaloh Mix (UA)

Last Updated 2/20/20