Insulin Lispro Protamine and Insulin Lispro

Dosage Forms

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)

Pharmacology

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.

Pharmacokinetics/Pharmacodynamics

Excretion

Urine

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

Time to Peak

Plasma: Humalog Mix 50/50: 0.75 to 13.5 hours; Humalog Mix 75/25: 0.5 to 4 hours

Duration of Action

14 to 24 hours

Use in Specific Populations

Special Populations: Renal Function Impairment

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

Use: Labeled Indications

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

Contraindications

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

Dosage and Administration

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: 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.

Administration

SubQ: 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.

Dietary Considerations

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

Storage

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.

Drug Interactions

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

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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: 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). Consider therapy modification

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

Maitake: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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. Consider therapy modification

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

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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. 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 Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. 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 Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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

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

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.

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)

Pregnancy

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.

Patient Education

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.