ATC Class: A10AB04
VA Class: HS501
Chemical Name: 28B-l-Lysine-29B-l-prolineinsulin (human)
Molecular Formula: C257H383N65O77S 6
CAS Number: 133107-64-9
Brands: HumaLOG, HumaLOG Mix 75/25
Antidiabetic agent; a rapid-acting biosynthetic human insulin analog.1 2 8 13 51 145
Uses for Insulin Lispro
Used to control hyperglycemia in the management of diabetes mellitus.1 2 3 6 12 47 75 77 78
In patients with type 1 diabetes mellitus, generally used in conjunction with an intermediate-acting or long-acting insulin preparation (i.e., isophane [NPH] insulin human, insulin lispro protamine [as the fixed combination Humalog Mix 75/25], insulin zinc [Lente], extended insulin human zinc [Ultralente]), to provide prandial glycemic control.1 73 74 76 77 78 79 81 96 144 145 159 160 161 165 In patients with type 2 diabetes mellitus, may be used without a longer-acting insulin when given with a sulfonylurea agent.1 158 159 160 161 165
Patients likely to benefit from insulin lispro therapy include type 1 diabetics who desire a more flexible injection schedule, those with low glycosylated hemoglobin values, and patients with recent-onset type 1 diabetes mellitus who have some residual β-cell function to provide basal insulin levels between meals.6 12 56 59 74 77 78 79 81 144 145
The effects of age, obesity, gender, and type of diabetes mellitus on glycemic response do not appear to differ in patients receiving insulin lispro versus insulin human.1 51
Some clinicians suggest that patients who are well-controlled on conventional short-acting insulin preparations without frequent hypoglycemia should not be routinely switched to insulin lispro.74 144
Insulin Lispro Dosage and Administration
Insulin lispro and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity.1 2 3 7 9 12 19 47 51 59
Any change in insulin should be made cautiously and only under medical supervision.1 Changes in insulin strength, manufacturer, type (e.g., regular, NPH), species (animal, human), or method of manufacture (rDNA versus animal-source insulin) may necessitate a change in dosage.1
Monitor patients through regular laboratory evaluations, including fasting blood (or plasma) glucose determinations, to assess therapeutic response and obtain the minimum effective dosage of insulin lispro.1 20 24 Whenever possible, patients should self-monitor blood glucose concentrations.1 5 19 22 51 60 Following initiation of insulin lispro therapy and dosage titration, determine glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations at intervals of approximately 3 months.22 24 144 145
Transferring from Therapy with Other Insulins
Make any change in insulin preparation or dosage regimen with caution and only under medical supervision.1 19 51
Not possible to clearly identify which patients will require a change in dosage when therapy with a different preparation is initiated.6 9 12 19 51
When switching from insulin human (regular) in regimens consisting of multiple insulin doses, use the previous insulin (regular) dosage as the initial dosage of insulin lispro.1 72 74 147 Subsequent dosage adjustments may be required due to changes in insulin purity, strength, brand, type, species source, or method of manufacture.1 2 3 7 9 12 19 47 51 59 Adjustments may be needed with the first dose or over a period of several weeks.1
When switching from insulin human (regular) in combination with a longer-acting insulin, dosage adjustment of the longer-acting insulin may be required.1 12 51 58 75 77 78 147 154
Patients receiving intensive insulin therapy (≥3 insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) will achieve greater postprandial glycemic control than those receiving conventional therapy because of the increased use of rapid- or short-acting insulin.6 9 22 59
Patients who previously were inadequately controlled on conventional insulin therapy generally will require a smaller total daily insulin dosage when switched to an intensive insulin regimen.6 9 22 59
Administer by sub-Q injection or continuous sub-Q infusion.1
Do not administer insulin lispro in fixed combination with insulin lispro protamine IV.a
To improve accuracy of dosing in pediatric patients, may be diluted to a ratio of 1:10 or 1:2 with the sterile diluent supplied by the manufacturer.1
For solution and drug compatibility information, see Compatibility under Stability.
Administer by sub-Q injection immediately (i.e., within 15 minutes before or after a meal) using a conventional insulin syringe or an injection pen (e.g., Becton-Dickinson [B-D] Pen, Humalog Pen, Novo Nordisk’s NovoPen).1 19 155 156 157
Generally administered in multiple daily doses in regimens that also include an intermediate- or long-acting insulin (e.g., NPH, Lente, Ultralente) given in the morning and/or evening to provide basal insulin needs.1 72 74
Administer insulin lispro in fixed combination with insulin lispro protamine (Humalog Mix 75/25) twice daily within 15 minutes prior to the morning and evening meal.159 161
Administer into abdominal wall, thigh, or upper arm.g To avoid tissue damage, give the next injection at least 1/2 inch from the previous injection site.g
Administer by continuous sub-Q infusion using an external controlled-infusion device.1 Recommended for use in Disetronic H-TRONplus V100 (with Disetronic 3.15 mL insulin reservoir), Disetronic D-TRON, or Disetronic D-TRONplus external infusion pumps with Disetronic Rapid infusion sets and in MiniMed model 506, 507, or 508 pumps with MiniMed Polyfin infusion sets.1 Delivers rapid- or short-acting insulin at a basal rate continuously throughout the day, with patient-initiated delivery of insulin prior to meals.27 28
Dosage of insulin lispro is always expressed in USP units.1 19 20 22 23 24 38 62 63
Individualize dosage; adjust dosage regularly based on blood glucose determinations.1 n Usually, the total daily insulin requirement in children with type 1 diabetes mellitus ranges from 0.2–1 units/kg (generally 0.5–0.8 units/kg daily).22 28 47 z Adolescents in a growth phase may require an initial insulin dosage of 1–1.5 units/kg daily.28 No specific dosage recommendations by manufacturer.1 When used as a preprandial treatment regimen in clinical trials, 26–64% of total insulin requirements have been provided by insulin lispro, with the remainder provided by an intermediate-acting or long-acting insulin.n o q t u
Individualize dosage; adjust dosage regularly based on blood glucose determinations.1 Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.1
No specific dosage recommendations by manufacturer.1 In a clinical trial, preprandial administration of insulin lispro injection comprised approximately 66% of the total daily insulin dosage, with the remainder given as a basal infusion.q
Individualize dosage; adjust dosage regularly based on blood glucose determinations.1 Usually, the total daily insulin requirements in patients with type 1 diabetes mellitus is 0.5–1 unit/kg.h No specific dosage recommendations by manufacturer.1 When used in a preprandial treatment regimen in clinical trials, 39–66% of total insulin requirements have been provided by insulin lispro, with the remainder provided by an intermediate-acting or long-acting insulin.147 i j k l r
In patients with type 2 diabetes mellitus who are not controlled on intermediate-acting or long-acting insulin, some clinicians suggest initiating preprandial therapy with a short-acting or rapid-acting insulin, with the preprandial injection comprising 40–50% of the total insulin dosage.p
Individualize dosage; adjust dosage regularly based on blood glucose determinations.1 Glucose monitoring is particularly important for patients receiving insulin via an external infusion pump.1
No specific dosage recommendations by the manufacturer.1 In patients with type 1 diabetes mellitus, preprandial administration of insulin lispro injection has been used in clinical trials, comprising approximately 21–46% of the total daily insulin dosage, with the remainder given as a basal infusion.168 m r s
Therapy with Fixed-Combination Insulin Lispro and Insulin Lispro ProtamineSub-Q Injection
Individualize dosage; adjust dosage regularly based on blood glucose determinations.a
No specific dosage recommendations by the manufacturer.a Initially, 0.3–0.5 units/kg daily given in 2 divided doses (before morning and evening meal) has been used in patients with type 2 diabetes mellitus.v y Subsequent dosage has been titrated in increments of 2–4 units per injection per day every 2–3 days to achieve the targeted fasting blood glucose concentration.v y Mean daily maintenance insulin dosage achieved was 0.46–0.66 units/kg.159 v w x y
In patients with type 1 diabetes mellitus in a clinical trial, mean daily maintenance insulin dosage achieved was 0.64 units/kg.x
Renal and Hepatic Impairment
Careful monitoring of blood glucose and dosage adjustment may be necessary.1
Cautions for Insulin Lispro
Use of insulin lispro during episodes of hypoglycemia.1
Known hypersensitivity to insulin lispro or any of its excipients.1
Insulin lispro has a more rapid onset and shorter duration of action than insulin human (regular).1 Patients with type 1 diabetes require a longer-acting insulin to maintain adequate nighttime and preprandial blood glucose control.1 74 76 77 78 79 81 144
Care should be taken in patients who are most at risk for the development of these effects, including patients who are fasting or those with defective counterregulatory responses (e.g., patients with autonomic neuropathy, adrenal or pituitary insufficiency, those receiving β-adrenergic blocking agents).
Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.1 Homeostatic responses become defective, and early warning signs of hypoglycemia may be diminished or absent in patients with long-standing type 1 diabetes mellitus, diabetic neuropathy,1 and/or those receiving drugs such as β-adrenergic blocking agents that mask catecholamine-induced manifestations of hypoglycemia (e.g., tremors, palpitations).1
Use intensive insulin therapy with caution in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes. Higher target blood glucose concentrations (e.g., fasting blood glucose concentrations of 140 mg/dL and 2-hour postprandial concentrations of 200–250 mg/dL) are advisable in these patients.
Local reactions (e.g., erythema, pruritus, swelling) reported.1 Generalized hypersensitivity reactions (e.g., rash, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis) reported less frequently; may be life-threatening.1
Localized reactions and generalized myalgias reported with the use of m-cresol, an excipient in the formulation.1
Insulin lispro is no more immunogenic than insulin human.12 14 15 17 18 51 52
Weigh benefits versus risks in patients with a history of hypersensitivity to other insulins.51
Atrophy or hypertrophy of subcutaneous fat tissue may occur at sites of frequent insulin injections.1 Changing injection technique may reduce or prevent these effects.g
Care should be taken in patients who are most at risk for the development of hypokalemia, such as those who are receiving potassium-lowering drugs.a
Not known whether insulin lispro is distributed into milk, however, other insulins (e.g., insulin human) are distributed into milk.1 1 Caution if used in nursing women.1 Adjustments in insulin lispro dosage and/or meal plans may be required.1
Safety and efficacy of insulin lispro in fixed combination with insulin lispro protamine not established in children <18 years of age.165
Insulin lispro has been used in children aged 3–18 years of age with type 1 diabetes mellitus,1 51 74 and preliminary data suggest no unusual effects of insulin lispro therapy in adolescents receiving the drug.74 118 144 145 149 150 151 Adjustment of basal insulin dosages may be required.1
Safety of intensive insulin regimens in geriatric patients has been questioned. Increased incidence of hypoglycemia associated with intensive insulin therapy may increase the probability of strokes and heart attacks in such patients.
Hypoglycemic reactions may mimic a cerebrovascular accident.d Patients with type 2 diabetes mellitus may be more vulnerable to serious consequences of hypoglycemia (e.g., fainting, seizures, falls, stroke, silent ischemia, MI, or sudden death) due to an increased incidence of macrovascular disease.
Response in patients ≥65 years of age does not appear to differ from that in younger adults.1
Common Adverse Effects
Interactions for Insulin Lispro
Drugs That May Potentiate Hypoglycemic Effects
Oral antidiabetic agents
Somatostatin derivatives (e.g., octreotide)
Drugs That May Antagonize Hypoglycemic Effects
Estrogens and progestins (e.g., oral contraceptives)
Sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline)
Drugs That May Have a Variable Effect on Glycemic Control
β-Adrenergic blocking agents
Drugs That May Reduce or Eliminate Signs of Hypoglycemia (Sympatholytic Agents)
β-Adrenergic blocking agents
Insulin Lispro Pharmacokinetics
Following sub-Q administration, more rapidly absorbed than soluble preparations of insulin human or insulins of animal origin.1 2 3 6 9 10 51 73 144 145 165
Peak plasma insulin concentrations are higher and occur earlier with insulin lispro (at 30–90 minutes) than with insulin human (at 50–120 minutes).1 2 6 9 10 11 73 165
Following sub-Q administration of the fixed combination of insulin lispro and insulin lispro protamine (Humalog Mix 75/25), peak serum insulin concentrations were observed at 30–240 minutes (median: 60 minutes).165 More rapidly absorbed than the fixed combination of insulin human (regular) and isophane insulin human (Humulin 70/30).165
Many factors can affect the onset, degree, and duration of insulin activity (e.g., injection technique, presence of insulin antibodies, site of injection, tissue blood supply, temperature, excipients in insulin formulations, and interindividual and intraindividual differences in response).1 19 47 74 83
Following sub-Q injection of insulin lispro, onset generally ranges from 0.25–0.5 hours versus 0.5–1 hours for insulin human, respectively.1 3 9 51 73 74 83 Peak glycemic response for insulin lispro or insulin human occurs at 0.5–2.5 or 1–5 hours, respectively.1 3 9 51 73 74 83
Following sub-Q administration, the duration of hypoglycemic action of insulin lispro is 3–6.5 hours compared with 6–10 hours for insulin human.47 51 73 74 83
The duration of action of Humalog Mix 75/25 is similar to that of Humulin 70/30.165
Administer 15 minutes before or immediately after meals.1 72
The presence of hepatic impairment does not affect the absorption in patients with type 2 diabetes mellitus.1
Not known whether insulin lispro is distributed into human milk; however, other insulins (e.g., insulin human) are distributed into milk.1 Does not appear to cross the placenta in pregnant women with gestational diabetes.164
The volume of distribution of insulin lispro reportedly is identical to that of insulin human and ranges from 0.26–0.36 L/kg.1
Hepatic impairment does not affect the distribution in patients with type 2 diabetes mellitus.1
Metabolic fate has not been determined in humans.1 165 In animals, metabolism of insulin lispro is identical to that of insulin human.1 165
Insulin is rapidly metabolized mainly in the liver and to a lesser extent in the kidneys and muscle tissue.d
1 or 1.5 hours for insulin lispro or insulin human, respectively.2 51
Circulating insulin concentrations may be increased in patients with renal or hepatic failure.1
Injection, for Sub-Q Use
With unopened vials, disposable injection pens, or cartridges of the drug that have not been placed in a delivery device, 2–8°C.1 19 156 165 Do not freeze; discard vial or cartridge if frozen.1 19 156 165
With vials, pens, or cartridges of insulin lispro that cannot be refrigerated or vials, cartridges, and disposable injection pens that are in use, <30°C for up to 28 days.1 19 51 81 155 Protect from heat and light.1 155
With disposable injection pens of insulin lispro in fixed combination with insulin lispro protamine (Humalog Mix 75/25 Pen) that are in use, room temperature for up to 10 days.160 165 Protect from light and excessive heat.160 165
When insulin lispro is diluted with the sterile diluent for pediatric use, discard the diluted solution after 28 days when stored at 5°C or after 14 days when stored at 30°C.165
Should not expose insulin lispro in the external infusion device to temperatures >37°C during administration.1 Replace infusion sets (reservoir syringe, tubing, and catheter), the DisetronicD-TRON or DisetronicD-TRONplus cartridge adapter, and insulin lispro in the pump reservoir and select a new infusion site at least every 48 hours.1 Should discard the 3-mL cartridges used in the DisetronicD-TRON or DisetronicD-TRONplus insulin pumps after 7 days, even if some drug still remains in the reservoir.1
Simulated administration of insulin lispro by continuous sub-Q infusion in several external infusion pump systems (i.e., Disetronic H-TRON, Minimed Model 504 pumps) revealed no changes in the potency, purity, or physical stability of the drug when stored within each of these devices for 48 hours.51 81 146 163 However, precipitation of insulin lispro on infusion catheters (i.e., Silhouette, Soft-Set catheters) has been noted in several patients who were receiving insulin lispro via one of several external pump systems (i.e., Disetronic H-TRON V-100, Minimed 507C pumps).167
For information on systemic interactions resulting from concomitant use, see Interactions.
When insulin lispro is mixed with a longer-acting insulin preparation, insulin lispro should be drawn into the syringe first in order to prevent precipitation or turbidity of the insulin lispro solution by the longer-acting insulin.1 Insulin mixtures should not be administered IV.1
Should not dilute or mix insulin lispro with any other insulin when administered via an external sub-Q controlled-infusion device (pump).1
Extended human insulin zinc
Insulin, isophane human (recombinant DNA origin)
Facilitates cellular uptake of glucose in muscle and other tissues, except the brain.c d Stimulates protein synthesis and inhibits protein catabolism.1 d
Inhibits output of glucose from the liver.9 c d In the liver, insulin facilitates phosphorylation of glucose to glucose-6-phosphate which is converted to glycogen or further metabolized.d Promotes the conversion of excess glucose into fat.1
Stimulates lipogenesis and inhibits lipolysis and release of free fatty acids from adipose cells.d
Promotes an intracellular shift of potassium and thereby appears to temporarily decrease elevated blood concentrations of this ion.d
Advice to Patients
Importance of providing the patient with a copy of the manufacturer’s patient information.1 2 23 26
Importance of providing instructions regarding insulin storage, dosage, and proper injection technique.1 e
Importance of strict adherence to manufacturer’s instructions regarding assembly, administration, and care of specialized delivery systems, such as insulin pens.72 144 145 e
Importance of changing insulin preparation or dosage with caution and only under medical supervision.1 19 51 Discuss potential for alterations in insulin requirements and need for additional monitoring of blood glucose concentrations in special situations (e.g., illness, concomitant agents that alter glycemic control, travel, emotional disturbances, or other stresses).
Advise patients of the risks and advantages of conventional and intensive insulin therapy.
Importance of administering insulin lispro sub-Q within 15 minutes before or immediately after a meal.1
Advise patient not to smoke within 30 minutes after insulin injection, due to potential for decreased absorption of insulin.e
Importance of carefully advising patients of the differences in action profiles between insulin lispro and insulin human (regular) during transfer from insulin human to insulin lispro.1 74 May be necessary to adjust the consumption and/or timing of snacks or exercise to avoid hypoglycemic episodes and/or prevent preprandial hyperglycemia.1 74
Importance of regular self monitoring of blood glucose concentrations.1 e Particular importance of frequent self monitoring of blood glucose concentrations in patients with a history of hypoglycemic unawareness or recurrent, severe hypoglycemic episodes.
Provide instructions regarding adherence to meal planning, regular physical exercise, periodic HbA1c monitoring, and management of hypoglycemia or hyperglycemia.1 e
Importance of wearing a medical identification bracelet or pendant, carrying ample insulin supply and syringes on trips, and having carbohydrates (sugar or candy) on hand for emergency.e
Importance of not changing the order of mixing insulins or the model or brand of syringe or needle without medical supervision.1 e When mixing with long-acting insulin preparations, importance of drawing insulin lispro into the syringe first.e
Importance of informing clinicians of the development of generalized hypersensitivity reactions (shortness of breath, hypotension, wheezing, whole body rash, tachycardia, diaphoresis).1
Importance of patients being aware of symptoms of diabetic ketoacidosis and the need to monitor blood ketones if preprandial blood glucose concentrations repeatedly exceed 250–300 mg/dL or if they have an acute illness. Importance of contacting a physician if results of self-monitored blood glucose concentrations are consistently abnormal.
Inform patient that use of marijuana may increase insulin requirements.e
Instruct patient on the appropriate measures for safe disposal of needles.e
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
HumaLOG (with cresol, glycerin and zinc oxide; available as 1.5-mL cartridge, 3-mL disposable delivery device, and 10-mL vial)
Insulin Lispro 25 units/mL with Insulin Lispro Protamine 75 units/mL
HumaLOG Mix 75/25 (with m-cresol, glycerin, and zinc oxide; available as 3-mL delivery device)
AHFS DI Essentials. © Copyright 2018, Selected Revisions February 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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