Insulin Lispro Protamine and Insulin Lispro
(IN soo lin LYE sproe PROE ta meen & IN soo lin LYE sproe)
- Insulin Lispro and Insulin Lispro Protamine
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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)
Brand Names: U.S.
- HumaLOG Mix 50/50
- HumaLOG Mix 50/50 KwikPen
- HumaLOG Mix 75/25
- HumaLOG Mix 75/25 KwikPen
- Insulin, Combination
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.
Onset of Action
0.25-0.5 hours; Peak effect: Humalog Mix 50/50: 0.8-4.8 hours; Humalog Mix 75/25: 1-6.5 hours
Time to Peak
Plasma: Humalog Mix 50/50: 0.75-13.5 hours; Humalog Mix 75/25: 0.5-4 hours
Duration of Action
Special Populations: Renal Function Impairment
Insulin Cl may be reduced in patients with impaired renal function.
Use: Labeled Indications
Treatment of type 1 diabetes mellitus (insulin dependent, IDDM) and type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control
Hypersensitivity to any component of the formulation; during episodes of hypoglycemia
Diabetes mellitus: 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. Fixed ratio insulins (such as insulin lispro protamine and insulin lispro combination) are typically administered as 2 daily doses with each dose intended to cover two meals and a snack. 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.
Diabetes mellitus, type 1: SubQ:
General insulin dosing:
Note: Multiple daily doses are utilized and guided by blood glucose monitoring. Combinations of different insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined. 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.
Usual maintenance range: SubQ: 0.5 to 1 units/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:
Nonobese: 0.4 to 0.6 units/kg/day
Obese: 0.8 to 1.2 units/kg/day
Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF-ISPAD, 2011).
Division of daily insulin requirement ("conventional therapy"): Generally, 50% to 75% of the daily insulin dose is given as an intermediate- or long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the 24-hour insulin requirement is divided and administered as either regular insulin or a rapid-acting form of insulin at the same time before breakfast and dinner.
Adjustment of dose: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.
Diabetes mellitus, type 2: SubQ: Augmentation therapy (patients for which diet, exercise, weight reduction, and oral hypoglycemic agents have not been adequate): Note: 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. Dosage must be carefully adjusted.
General considerations for insulin use in type 2 diabetes:
Timing of initiation: The goal of therapy is to achieve an HbA1c <7%. According to a position statement by the ADA and European Association for the Study of Diabetes (EASD), dual therapy (metformin + a second antihyperglycemic agent) is recommended in patients with type 2 diabetes who fail to achieve glycemic goals after ~3 months with lifestyle interventions and metformin monotherapy (unless contraindications to metformin exist). Preference is not given for adding insulin or a noninsulin agent as the second antihyperglycemic agent (drug choice should be individualized based on patient characteristics). However, insulin should be considered as part of a combination regimen when hyperglycemia is severe, particularly if patient is symptomatic or has catabolic features (eg, weight loss, ketosis). If insulin is selected, the addition of basal insulin (ie, a long-acting insulin such as glargine or detemir) is recommended. If HbA1c target not achieved after ~3 months of dual therapy, may proceed to triple therapy (Inzucchi 2015).
Intensification of therapy: If HbA1c target has not been met, despite titrating basal insulin (ie, long-acting insulin) to provide acceptable fasting blood glucose concentrations, intensification of therapy should be considered to cover postprandial glucose excursions. Options include adding a mealtime insulin (1 to 3 injections of a rapid-acting insulin analog [lispro, aspart, glulisine]) or adding a GLP-1 receptor agonist (eg, exenatide, liraglutide). Alternatively, although less studied, may transition from basal insulin (ie, long-acting insulin) to a twice daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix) (Inzucchi 2015).
Refer to adult dosing.
Dosing: Renal Impairment
No dosage adjustment 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
No dosage adjustment provided in manufacturer’s labeling; insulin requirements may be reduced due to changes in insulin clearance or metabolism; monitor blood glucose closely.
Refer to indication-specific dosing for obesity-related information (may not be available for all indications).
SubQ administration: 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. Insulin lispro protamine and insulin lispro combination products should be administered within 15 minutes before a meal; typically given once- or twice daily. SubQ administration is usually made into the thighs, arms, buttocks, or abdomen; rotate injection sites within the same region to avoid lipodystrophy. Do not dilute or mix with any other insulin formulation or solution; not recommended for use in external SubQ insulin infusion pump.
Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Compatibility in syringe: Incompatible with insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin NPH, insulin regular.
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.
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 Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy
DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification
Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy
Edetate Disodium: May enhance the hypoglycemic effect of Insulin. Monitor therapy
GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification
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 Insulin. 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
MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Metreleptin: May enhance the hypoglycemic effect of Insulin. 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
Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy
Pioglitazone: May enhance the adverse/toxic effect of Insulin. 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 Insulin. 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
Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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
Rosiglitazone: Insulin 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
SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. 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
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
Concerns related to adverse effects:
• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin detemir, insulin glargine) may delay recovery from 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.
• 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.
• 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.
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).
• Administration: Insulin lispro protamine and insulin lispro premixed combination products are NOT intended for IV or IM administration
• Appropriate use: Diabetes mellitus: The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- [insulin lispro protamine and insulin lispro] or long-acting insulin via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Since treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient’s impaired glycemic control. Treatment and monitoring regimens must be individualized.
• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
Diabetes mellitus: Plasma glucose, 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 2016a])
Pregnancy Risk Factor
Adverse events have not been observed in animal reproduction studies. Insulin lispro has not been shown to cross the placenta at standard clinical doses (Boskovic 2003; Holcberg 2004; Jovanovic 1999).
In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2016d; Kitzmiller 2008; Metzger 2007). 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 (ACOG 2013; ADA 2016d; Blumer 2013; Kitzmiller 2008; Lambert 2013). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (ADA 2016d; Kitzmiller 2008).
Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks of gestation. Following delivery, insulin requirements decrease rapidly (ACOG 2005).
Prior to pregnancy, women with diabetes who are trying to conceive should be treated with multiple daily doses of insulin or continuous subcutaneous insulin infusion (CSII) as opposed to split-dose, premixed insulin therapy. This is to allow for better glucose control and flexibility during pregnancy (Blumer 2013).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), severe injection site irritation, vision changes, chills, severe dizziness, passing out, mood changes, seizures, slurred speech, shortness of breath, excessive weight gain, swelling of arms of legs, or change in skin to thick or thin at injection site (HCAHPS).
• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.