ATC Class:A10AB04

VA Class:HS501

AHFS Class:

• Rapid-acting Insulins 68:20.08.04

Generic Name(s):

• Insulin Lispro

Chemical Name:

• 28^B-l-Lysine-29^B-l-prolineinsulin (human)

Molecular Formula:

• C₂₅₇H₃₈₃N₆₅O₇₇S ₆

Insulin lispro is a rapid-acting biosynthetic human insulin analog that is structurally identical to insulin human except for reversal of the sequence of lysine and proline on the B chain of the molecule; in insulin lispro, lysine and proline occur at positions 28 and 29, respectively, of the B chain.1,2,8,13,51,145

Diabetes Mellitus

Insulin lispro is a rapid-acting insulin analog that is used to control hyperglycemia in the management of diabetes mellitus.1,2,3,6,12,47,75,77,78,173 In patients with type 1 diabetes mellitus, insulin lispro generally is used in conjunction with a longer-acting insulin (except when administered via an external insulin infusion device [pump]); in patients with type 2 diabetes mellitus, insulin lispro may be used without a longer-acting insulin when given with an oral sulfonylurea antidiabetic agent.1,158,159,160,161,165 (See Combination Therapy under Uses: Diabetes Mellitus, in the Insulins General Statement 68:20.08.) When administered subcutaneously, insulin lispro has a more rapid onset and shorter duration of action compared with insulin human (regular); therefore, insulin lispro is associated with greater relative reductions in postprandial blood glucose concentrations and may provide greater patient convenience in terms of the timing of insulin injections in relation to meals in patients with type 1 and type 2 diabetes mellitus.3,9,10,11,12,51,56,73,74,75,77 Because of its short onset and duration of action, insulin lispro usually is used in regimens that include a longer-acting insulin (i.e., isophane [NPH] insulin human, insulin lisproprotamine [as the fixed combination Humalog^® Mix75/25^®, Humalog^® Mix50/50^®], insulin glargine) in an attempt to provide more physiologic insulin levels throughout the day.1,73,74,76,77,78,79,81,96,144,145,159,160,161,165,173,175

Insulin lispro also is administered by continuous subcutaneous infusion using selected external controlled-infusion devices (pumps) in patients with diabetes mellitus.1 Limited data in patients with type 1 diabetes mellitus suggest that continuous subcutaneous administration of insulin lispro provides greater glycemic control (as measured by glycosylated hemoglobin) than that provided by continuous subcutaneous administration of buffered human insulin or regular human insulin.1,170 These data indicate a similar incidence of hypoglycemia among patients receiving insulin lispro or regular or buffered human insulin via external infusion pumps.1 Available data suggest that continuous subcutaneous administration of insulin provides glycemic control similar to that provided by intensive, multiple-daily-dose insulin therapy.22,144,163 Insulin lispro administration via external controlled-infusion devices has not been studied in patients with type 2 diabetes mellitus.1,170

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes).86,87,88 Type 1 diabetes mellitus previously was described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth.88 Type 2 diabetes mellitus previously was described as adult-onset (AODM) diabetes mellitus.86 However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset.86,87,88 Many patients' diabetes mellitus does not easily fit into a single classification.177 Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus.166

Comparative clinical studies in patients with type 1 or type 2 diabetes mellitus who received insulin lispro or insulin human (regular) indicate that insulin lispro is associated with improved control of postprandial blood glucose concentrations.1,3,5,6,12,55,59,73,74,75,77,78 However, while therapy with insulin lispro was associated with reduced postprandial (e.g., post-breakfast) blood glucose excursions in these patients, overall glycemic control (as measured by hemoglobin A_1c values) did not differ appreciably from that in patients receiving insulin human (regular).1,11,12,55,59,75,77,78,79 The clinical importance of increased glycemic control of postprandial glucose excursions in nonpregnant diabetic patients with similar glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values has not been established.1,6,11,12,78,79,145 Most comparative studies of insulin lispro and insulin human (regular) were of open, crossover design in which patients received either insulin lispro within approximately 15 minutes before a meal or insulin human (regular) 20-45 minutes before a meal in addition to an intermediate-acting (e.g., NPH insulin) or long-acting (Ultralente^®) insulin as the basal insulin supplement.59,73,75,77,78 Main efficacy end points were 1-2 hour-postprandial blood glucose concentrations, glycosylated hemoglobin concentrations, frequency of hypoglycemia, and quality-of-life measures.59,73,75,77,78 However, in most of the larger studies conducted to date, patients were evaluated for only 3 months, which some clinicians state may not have been a sufficient period in which to assess changes in glycosylated hemoglobin.12,34,47,77,78,79,144 Since the duration of action of insulin lispro is brief, some clinicians have suggested that basal (e.g., intermediate-acting) insulin dosage be optimized to reflect the short duration of action of insulin lispro.74,76,77,78,79,81,91,96,147,148 The dosage or frequency of administration of the longer-acting insulin may be increased or the evening dose of longer-acting insulin may be delayed until bedtime; continuous subcutaneous infusion of insulin also may be used to manage increased preprandial and nighttime glucose concentrations (as compared with insulin human [regular]) observed with insulin lispro.74,76,77,78,79,81,91,96,144,145

Some clinicians suggest that patient-related factors such as motivation and knowledge of the disease may be more important in determining glycemic control than the type of insulin or insulin regimen used, and 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 Patients likely to benefit from insulin lispro therapy include type 1 diabetics who would appreciate the more flexible injection schedule associated with insulin lispro's shorter onset and duration of activity, those with low glycosylated hemoglobin values who are at high risk for hypoglycemic episodes, 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

Insulin lispro therapy generally has been associated with a reduced frequency of hypoglycemic episodes compared with insulin human (regular) in patients with type 1 diabetes mellitus and no change in hypoglycemic episodes in type 2 diabetics.73,74 In parallel-group clinical trials of insulin lispro and insulin human (regular) in patients with type 1 or type 2 diabetes mellitus, the overall incidence of hypoglycemia was not significantly different among patients receiving either of the 2 insulin preparations; however, patients with type 1 diabetes receiving insulin lispro had fewer late hypoglycemic episodes (i.e., between 12 midnight and 6 a.m.) than those receiving insulin human (regular), possibly because of higher nocturnal blood glucose concentrations (as reflected by a small increase in fasting blood glucose concentrations).1,75,77,78

Limited evidence suggests that insulin lispro also may be effective in establishing glycemic control in patients with resistance to insulin human.53,82 Transfer from insulin human (regular) to insulin lispro resulted in a reduction in insulin requirements in a patient with excessive insulin antibodies whose response was refractory to insulin human (regular).82,117 Further study and experience are needed to determine whether insulin lispro has clinical advantages over regular insulin for the long-term management of diabetes mellitus.12,51,58,144

For further information on indications for insulin therapy and considerations in selecting and monitoring such therapy in patients with diabetes mellitus, see the Insulins General Statement 68:20.08.

Administration

Insulin lispro is administered by subcutaneous injection using a conventional insulin syringe or an injection pen (e.g., Humalog^® Pen, Owen Mumford Autopen^®).1,19,155,156,157,165,171,173 Whenever possible, insulin should be self-administered by the patient.19 Patients should be instructed regarding proper administration and dosage of insulin lispro and given a copy of the patient information provided by the manufacturer.1,72 To improve accuracy of dosing in pediatric patients, insulin lispro may be diluted to a ratio of 1:10 or 1:2 with the sterile diluent supplied by the manufacturer.1 Use of injection pens may improve accuracy of insulin delivery and be more convenient in patients who are visually or neurologically impaired or who are receiving multiple daily injections of insulin.19,57,157 When a compatible delivery device is used for subcutaneous injection of insulin lispro, the labeling accompanying the delivery device should be consulted for proper methods of assembly, administration (including dose calibration), and care.72,144,145

The manufacturer states that insulin lispro in fixed combination with insulin lispro protamine suspension (Humalog^® Mix50/50^®, Humalog Mix75/25^®) is intended only for subcutaneous administration and should not be given IV.160,165,173 Before injecting the fixed combination of insulin lispro and insulin lispro protamine suspension using the injection pen, the pen should be rolled between the palms 10 times.160,174 The pen should then be turned upside down so that the glass ball inside the pen moves the length of the pen.160,174 This rolling and turning of the pen should be repeated at least 10 times or until the suspension appears to be uniformly white and cloudy.160,174

Insulin lispro also is administered by continuous subcutaneous infusion using selected external controlled-infusion devices (pumps).1,51,53,76,81,117,144,167,169 The pumps deliver rapid- or short-acting insulin at a basal rate continuously throughout the day, with patient-initiated increased delivery of insulin prior to meals.27,28 The manufacturer states that insulin lispro is recommended for use in Disetronic H-TRON^®plus V100 (with Disetronic 3.15-mL insulin reservoir), Disetronic D-TRON^®, or Disetronic D-TRON^®plus external infusion pumps with Disetronic Rapid^® Infusion sets and in MiniMed model 506, 507, or 508 pumps with MiniMed Polyfin^® infusion sets.1

The safety and efficacy of insulin lispro following IV administration†, such as in the treatment of diabetic ketoacidosis, has not been adequately evaluated to date.51,73 Insulin lispro's favorable pharmacokinetic profile compared with insulin human (regular) is based on its more rapid subcutaneous absorption rather than on more rapid post-absorptive uptake to insulin receptor sites, and no clinical advantage of IV insulin lispro compared with IV insulin human (regular) has been identified.51 While insulin lispro and insulin human have similar hypoglycemic effects when given IV†,1,15,51,73,74 the manufacturer states that insulin lispro is intended for subcutaneous administration and that insulin human (regular) should be used when IV administration of insulin is required.1,51,144 Some clinicians suggest that insulin lispro should not be used IV, especially in patients with diabetic ketoacidosis, as data are limited concerning the IV use of insulin lispro.51,73,144,145

The manufacturer states that the safety and efficacy of insulin lispro following IM† administration has not been evaluated in clinical trials.51

For additional information concerning insulin administration, see Dosage and Administration: Administration, in the Insulins General Statement 68:20.08.

When used as a mealtime insulin alone or in fixed combination with isophane insulin human to control postprandial hyperglycemia, insulin lispro should be administered within 15 minutes prior to a meal.1,72,160,165,173,174 Because of its short duration of action, insulin lispro is used concomitantly with, but not necessarily administered at the same time as, a longer-acting insulin (e.g., isophane [NPH] insulin human) to meet basal insulin needs in patients with type 1 diabetes mellitus and to provide more optimal glycemic control.1,19,121,144 Insulin lispro alone or in fixed combination with isophane insulin human can be administered by subcutaneous injection into the abdominal wall, thigh, or upper arm.1,160,173,174 A planned rotation of injection sites within an area (injections should be spaced at least 0.5 inch from a previous injection site) should be followed.72,160,174

Conflicting data have been reported regarding the effects of mixing insulin lispro and a longer-acting insulin on the pharmacodynamic effects of insulin lispro.1,73,74,79,81,121,122,123 Some data in healthy individuals indicate that mixing insulin lispro (Humalog^®) and NPH insulin human (i.e., Humulin N^®) in the same syringe results in a decreased rate of absorption, but no change in total bioavailability, of insulin lispro; this finding may be attributable to adsorption of insulin lispro to excess protamine in the NPH insulin formulation.19,73,79,144,161 Clinical studies in patients with type 1 diabetes mellitus indicate that mixtures of insulin lispro (Humalog^®) and NPH insulin human (i.e., Humulin N^®) either improve or produce similar effects on postprandial glycemic control compared with separate injection of these insulins.19,74,121 Concomitant administration of insulin lispro and Ultralente^® (no longer commercially available in the US) insulin human in the same syringe reportedly did not affect the absorption of insulin lispro in healthy individuals who received these insulins immediately after mixing.1,122 The manufacturer states that the effect of mixing Humalog^® (insulin lispro) with insulins of animal origin (no longer commercially available in the US) or human insulins produced by other manufacturers (i.e., other than Lilly) has not been studied.1 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

Dosage

Dosage of insulin lispro, which is always expressed in USP units, must be based on the results of blood glucose determinations and carefully individualized to attain optimum therapeutic effects.1,19,20,22,23,24,38,62,63 ( Glucose concentrations in plasma generally are 10-15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations .)24,162 Patients should be monitored with 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 Urine glucose concentrations correlate poorly with blood glucose; therefore, urine glucose determinations should be used only when patients cannot or will not test blood glucose concentrations.28,144 Glucose monitoring is particularly important for patients receiving insulin lispro via an external infusion pump.1 Following initiation of insulin lispro therapy and dosage titration, determination of glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy.22,24,144,145

For additional information on monitoring and management of insulin therapy, see Dosage: Considerations in Monitoring Insulin Therapy, in Dosage and Administration in the Insulins General Statement 68:20.08.

Both conventional and intensive insulin treatment regimens have been used in patients with type 1 or severe type 2 diabetes mellitus.10,11,12,19,23,25 (See Glycemic Control and Microvascular Complications of Diabetes Mellitus, in Uses in the Insulins General Statement 68:20.08.) Insulin lispro generally is 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 Insulin lispro in fixed combination with insulin lispro protamine (Humalog^® Mix75/25^®) generally is administered twice daily with the morning and evening meal.159,161 Dosage of insulin lispro alone or in fixed combination with insulin lispro protamine must be based on the results of blood glucose determinations and carefully individualized to obtain optimum therapeutic effect.1,51,78,147,165 While absorption of insulin lispro is more rapid, and duration of action slightly shorter, when administered in abdominal compared with deltoid or thigh sites, variations in absorption related to site of administration are smaller with insulin lispro than with regular insulin when insulin lispro is not mixed with other insulins in the same syringe.1,11,12,51,74,83

Transferring from Therapy with Other Insulins

Any change in insulin preparation or dosage regimen should be made with caution and only under medical supervision.1,19,51 When insulin lispro replaces insulin human (regular) in regimens consisting of multiple daily insulin doses, the initial dosage of insulin lispro can be identical to the previous insulin (regular) dosage with subsequent adjustment as required.1,72,74,147 However, patients in whom insulin lispro is initiated should be carefully advised regarding the difference in action profiles between insulin lispro and insulin human (regular); adjustments in the consumption and/or timing of snacks or exercise relative to that with the use of insulin (regular) may be necessary to avoid hypoglycemic episodes and/or prevent preprandial hyperglycemia.1,74 While pharmacokinetic and pharmacodynamic studies indicate that insulin lispro and insulin human are equipotent on a unit-for-unit basis with regard to glucose-lowering activity, changes in insulin purity, strength, brand, type, and/or species source or method of manufacture may necessitate a change in insulin dosage.1,2,3,7,9,12,19,47,51,59 Although it is not possible to clearly identify which patients will require a change in dosage when therapy with a different preparation is initiated, it is known that a limited number of patients will require such a change.6,9,12,19,51 Adjustments may be needed with the first dose or over a period of several weeks.1

When insulin lispro is substituted for insulin human (regular) in patients receiving combination therapy with insulin human (regular) and a longer-acting insulin, adjustment of the dosage of the longer-acting insulin may be required because of the shorter duration of action of insulin lispro.1,12,51,58,75,77,78,147,154 Patients receiving intensive insulin therapy will achieve greater postprandial glycemic control than those receiving conventional therapy because of the increased use of rapid- or short-acting insulin; patients who previously were poorly 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

Dosage in Renal and Hepatic Impairment

Results from clinical trials in a limited number of patients with type 2 diabetes mellitus and renal or hepatic impairment who were receiving either insulin lispro or insulin human indicate that the pharmacokinetic differences between the 2 types of insulin generally were maintained.1,173 The presence of hepatic impairment does not affect the absorption or distribution of insulin lispro in patients with type 2 diabetes mellitus.1,173 However, increased circulating concentrations of insulin have been observed in patients with renal or hepatic impairment who were receiving insulin human; therefore, insulin lispro requirements may be reduced in these patients.1,145 Careful monitoring of blood glucose and adjustment of insulin lispro (alone or in fixed combination with isophane insulin human) dosage may be necessary in such patients.1,165,173

For further information on the chemistry and stability, uses, and dosage and administration of specific insulin preparations, see the individual monographs in 68:20.08.

Insulin lispro shares the toxic potential of other insulins, and the usual precautions of insulin therapy should be observed with insulin lispro.144,145 (See Cautions in the Insulins General Statement 68:20.08.) The overall frequency and severity of adverse reactions to insulin lispro appear to be similar to those associated with insulin human (regular).1,75,76,81

Hypoglycemia

In comparative studies in patients with type 1 or type 2 diabetes mellitus, the overall rate of hypoglycemic reactions with insulin lispro was similar1,75,76 or somewhat less than that with insulin human;12,59,77,78 the frequency of nocturnal hypoglycemic reactions in patients with type 1 diabetes mellitus is less among those receiving insulin lispro.1,74,77,78 The lower rate of hypoglycemia observed with insulin lispro may be related to its shorter duration of action, resulting in a slightly greater degree of fasting hyperglycemia compared with insulin human.1

Immunogenicity

Several studies have shown that insulin lispro is no more immunogenic than insulin human.12,14,15,17,18,51,52 In one study in patients with type 1 or type 2 diabetes mellitus receiving insulin lispro or insulin human for 12 months, insulin specific antibody titers at endpoint were no different for each of the 2 insulin preparations.12,52 In large clinical trials, formation of insulin lispro-specific antibodies was low in patients receiving insulin lispro, but cross-reactive antibodies were observed in patients receiving insulin human or insulin lispro.1,52 The largest increase in antibody levels during year-long trials was observed in patients with type 1 diabetes mellitus who were receiving insulin therapy for the first time.1,52 In one study in rhesus monkeys, insulin antibody titers (IgG type) were found in 1 of 4 monkeys immunized with 6 weekly injections of insulin lispro (up to 100 mcg) prepared in Freund's adjuvant and in none of the monkeys receiving insulin human or purified pork insulin in Freund's adjuvant; none of the monkeys developed elevated insulin antibody titers of IgE type.17 As insulin allergies are mediated primarily by IgE insulin antibodies, use of insulin lispro is not expected to pose an increased risk for the development of insulin allergies.17

Other Effects

Localized reactions and generalized myalgias have been reported with the use of m -cresol, which is included in the Humalog^®, Humalog^® Mix75/25^®, or Humalog^® Mix50/50^® (insulin lispro) formulations as an excipient.1,165,173

Precautions and Contraindications

Insulin lispro has a more rapid onset and shorter duration of action than insulin human (regular).1,173 Clinicians who prescribe rapid-acting insulins should be familiar with the indications, limitations, and patient-selection criteria for therapy with insulin to ensure appropriate patient management.22,24,26,35,37,38 Because insulin lispro has a short duration of action, patients with type 1 diabetes also require a longer-acting insulin to maintain adequate nighttime and preprandial blood glucose control.1,74,76,77,78,79,81,144,175

Patients should read carefully and follow instructions regarding use of subcutaneous insulin infusion devices (e.g., infusion pumps and accessories) and intensive insulin therapy with multiple injections.1 Patients using insulin infusion devices should inform clinicians of the development of skin reactions (erythema, pruritus, thickened skin) at infusion sites.1 If such reactions occur, a new infusion site should be selected.1 Malfunctioning of the external-controlled infusion device or infusion set or insulin degradation can lead to hyperglycemia or ketosis within a short time period.1,167 If such symptoms occur, prompt identification and correction of the cause is necessary.1 Interim therapy with subcutaneous injections with insulin may be required if the cause of the symptoms cannot be promptly determined.1 (See Insulin Regimens under Dosage and Administration: Dosage, in the Insulins General Statement 68:20.08.) Complications such as undetected interruptions in insulin delivery may result in more frequent and more rapid ketotic episodes or unexplained hyperglycemia compared with multiple daily injections.170

Any change in insulin should be made cautiously and only under medical supervision.1,173 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.1,173

The manufacturer states that insulin lispro alone or in fixed combination with isophane insulin human (Humalog^® Mix50/50^®, Humalog^® Mix75/25^®) is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to the drug or any of its excipients.1,165,173 Patients with a history of hypersensitivity to other insulins should be given insulin lispro only if the clinician has determined that the possible benefits outweigh the potential adverse effects.51 (See Cautions: Dermatologic and Sensitivity Reactions, in the Insulins General Statement 68:20.08.) Patients should seek immediate medical assistance if they experience a generalized allergic reaction after injection of insulin lispro.1

Pediatric Precautions

The safety and efficacy of insulin lispro in fixed combination with insulin lispro protamine in children younger than 18 years of age have not been established.165,173 However, clinical trials with insulin lispro are ongoing 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 In several long-term (e.g., 8-9 months) comparative studies evaluating insulin lispro and insulin human in children and adolescents with diabetes mellitus, insulin lispro (given either immediately before or after meals) was as effective as insulin human (given 30-45 minutes before a meal) in improving glycemic control as determined by glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations.1 Adjustment of basal insulin dosage may be required in these children.1 (See Cautions: Pediatric Precautions, in the Insulins General Statement 68:20.08.)

Geriatric Precautions

In clinical trials, the efficacy (as measured by HbA_1cvalues) of insulin lispro or incidence of hypoglycemia did not differ by age.1,155 Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of action of insulin lispro have not been performed.1 Subgroup analyses of large clinical trials have not revealed evidence of altered effectiveness of insulin lispro compared with insulin human based on age.1 However, some evidence suggests an increased risk of cardiovascular morbidity associated with hypoglycemia in geriatric patients receiving intensive insulin therapy.37,38,47,57,113 (See Cautions: Geriatric Precautions, in the Insulins General Statement 68:20.08.)

With insulin lispro in fixed combination with isophane insulin human, experience in those 65 years of age or older is insufficient to determine whether they respond differently from younger adults.165,173 However, dosage of insulin lispro in fixed combination with isophane insulin human should be selected carefully in geriatric patients, and the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.165,173

Mutagenicity and Carcinogenicity

No evidence of mutagenicity or chromosomal damage with insulin lispro was observed in vivo in a micronucleus test or chromosome aberration test or in in vitro test systems, including microbial (bacterial mutation tests) and mammalian (mouse lymphoma) assays.1 There was no increase in DNA repair when insulin lispro was tested in an unscheduled DNA synthesis test.1 . In addition, no evidence of carcinogenicity was observed in a study in rats receiving up to 200 units/kg daily of insulin lispro subcutaneously for 12 months.16

Pregnancy, Fertility, and Lactation

Pregnancy

Insulin lispro has been evaluated in a limited number of pregnant women with gestational diabetes.164 The American Diabetes Association (ADA) suggests that continuous subcutaneous insulin infusion with insulin lispro may improve glycemic control during pregnancy.163 Congenital abnormalities (including kidney dysplasia) have been reported in at least 2 infants of patients with type 1 diabetes mellitus who received insulin lispro and other insulins during pregnancy; a causal relationship to insulin lispro has not been established.119,120,145 Abnormal maternal blood glucose concentrations during pregnancy have been associated with a higher incidence of congenital abnormalities.7,93,104,119,152,153 Although glycemic control reportedly was well maintained during pregnancy in these women,119 optimization of glycemic control before conception and throughout pregnancy does not completely eliminate the risk of congenital anomalies.120,144 The manufacturer states that insulin lispro alone or in fixed combination with isophane insulin human should be used in pregnant women only when clearly needed.1,120,165,173

Reproduction studies of insulin lispro in pregnant rats and rabbits using parenteral dosages of up to 4 or 0.3 times, respectively, the average human dosage (40 units daily) have not revealed evidence of fetal malformations.1,7 Modest decreases in food consumption and weight gain, and occasional instances of severe hypoglycemia and death, were noted when insulin lispro was administered subcutaneously at a dosage of 20 units/kg daily to male rats prior to cohabitation through two consecutive matings and to female rats prior to cohabitation and through gestational day 19; these effects were expected based on the pharmacologic effects of the drug.7 Transient decreases in fetal and newborn pup weights and an increased incidence of fetal runts per litter suggested a marginal effect on in utero growth at an insulin lispro dosage of 20 units/kg daily; however, no effects on pup growth were observed with dosages of 1-5 units/kg daily.7

Fertility

Reproduction studies evaluating the effect of insulin lispro on fertility have not been conducted.1,145 Reproduction studies in male rats receiving subcutaneous injections of insulin lispro at doses up to 20 units/kg daily have not revealed evidence of impaired reproductive performance, testicular histopathology, or impaired fertility in the parental generation or in the untreated successive generation.7

Lactation

Insulin lispro alone or in fixed combination with isophane insulin human should be used with caution in nursing women, since it is not known whether the drug is distributed into milk in humans.1,165,173 However, other insulins (e.g., insulin human) are distributed into milk.1,165,173 Patients with diabetes who are lactating may require adjustments in insulin lispro (alone or in fixed combination with isophane insulin human) dosage, meal plans, or both.1,165,173

For additional information on the use of insulin in gestational diabetes mellitus and during the perinatal period, see Uses: Gestational Diabetes Mellitus and see Dosage: Insulin Use during Pregnancy, in the Insulins General Statement 68:20.20.

Pharmacology

Studies in animals, healthy adults, and patients with type 1 (insulin-dependent) diabetes mellitus indicate that insulin lispro has pharmacologic effects comparable to those of insulin human.1,2,3,7,12,51,54,59,73,74 165 The fixed combination of insulin lispro and insulin lispro protamine (Humalog^® Mix75/25^®) has glucose-lowering effects similar to those of the fixed combination of insulin human (regular) and isophane insulin human (Humulin^® 70/30) on a unit-for-unit basis.165

The potency of insulin lispro, with respect to its efficacy for replacement therapy in patients with type 1 diabetes mellitus, is similar to that of insulin human.1,2,3,7,12,51,59,81 165 Short-term, in vitro receptor-binding studies demonstrate that insulin lispro and insulin human have similar affinity for insulin receptor binding sites.2,3,18,51,74 However, the number and affinity of insulin receptors on circulating monocytes in a limited number of patients with type 1 diabetes mellitus increased to levels similar to those in healthy individuals following 3 months of therapy with insulin lispro, while patients receiving insulin human (regular) had a decrease in insulin receptor affinity and binding capacity.80,144 It has been suggested that the improvement in insulin receptor status during prolonged therapy with insulin lispro may be related to its more physiologic pharmacokinetic profile relative to that of regular insulin.80,144,145

Insulin lispro and insulin human have similar short-term hypoglycemic effects when given IV.1,15,51,73,74 In patients with type 1 diabetes mellitus in whom hypoglycemia was induced experimentally, the counterregulatory hormone response to hypoglycemia was similar with insulin lispro and insulin human; similar counterregulatory hormone responses to ingestion of a meal have been reported in other studies.6,9,11,15,74 Limited data suggest that insulin lispro suppresses hepatic glucose production and promotes peripheral glucose utilization to a greater extent than does insulin human when the drugs are given subcutaneously.9 In patients with type 1 diabetes mellitus who received insulin lispro or insulin human (regular) by continuous subcutaneous infusion for 3 months, glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) values and postprandial blood glucose concentrations were lower with insulin lispro therapy; however, timing of insulin human administration was not optimized since both insulin human and insulin lispro were administered within 5 minutes before meals.76,144 163 (See Insulin Regimens, under Dosage and Administration: Dosage in the Insulins General Statement 68:20.08.) The incidence of hypoglycemic episodes was lower than baseline levels and similar for both drugs.76

For further information on the pharmacology of insulin, see the Insulins General Statement 68:20.08.

Pharmacokinetics

Absorption

Insulin lispro is more rapidly absorbed than soluble preparations of insulin human or insulins of animal origin following subcutaneous administration because of its ability to dissociate faster from the insulin hexamer in solution.1,2,3,6,9,10,51,73,144,145,165 Absorption of other insulins (e.g., insulin human) from subcutaneous sites is delayed by the time required for dissociation of insulin hexamers into dimers and monomers that can diffuse into the systemic circulation.10,51,74,145 Therefore, insulin lispro has a faster onset and shorter duration of action than other insulins and, when administered subcutaneously 15 minutes before a meal, more closely mimics the endogenous postprandial insulin response.2,3,6,9,10,11,18,51,145,165 After subcutaneous administration of 0.1-0.4 units/kg of insulin lispro or insulin human in healthy individuals or patients with type 1 diabetes mellitus, 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 Addition of zinc to the commercially available formulation of insulin lispro reduces peak serum concentrations somewhat compared with an insulin lispro formulation without zinc (not commercially available in the US) but does not appreciably alter the time to peak concentration.3,51 Unlike with insulin human, the time to peak serum concentration following subcutaneous administration of insulin lispro does not increase with increasing doses.74 Serum concentrations of insulin lispro also exhibit less intraindividual and interindividual variability than those of insulin human, possibly because of differences in the intrinsic properties of these insulins.1,3,74

The fixed combination of insulin lispro and insulin lispro protamine (Humalog^® Mix75/25^®, Humalog^® Mix50/50^®) exhibits 2 phases of absorption.165,173 The early phase represents insulin lispro and its rapid onset of action; the late phase represents the prolonged action of insulin lispro protamine suspension.165,173 In a limited number of nondiabetic individuals, peak serum insulin concentrations were observed 30-240 minutes (median: 60 minutes) following subcutaneous administration of the fixed combination (0.3 units/kg) of insulin lispro and insulin lispro protamine (Humalog^® Mix75/25^®); results were identical in diabetic patients.165 In patients with type 1 diabetes mellitus, peak serum (immunoreactive) insulin concentrations were observed at 45-120 minutes (median: 60 minutes) following administration of the Humalog^® Mix50/50^® fixed combination.173 The fixed combinations of insulin lispro and insulin lispro protamine (Humalog^® Mix75/25^®, Humalog^® Mix50/50^®) are absorbed more rapidly than the fixed combination of insulin human (regular) and isophane insulin human (Humulin^® 70/30^®, Humulin^® 50/50), including in patients with type 1 diabetes mellitus.165,173 The duration of action of Humalog^® Mix75/25^® and Humalog^® Mix50/50^® also is similar to that of Humulin^® 70/30^® and Humulin^® 50/50^®.165,173

The pharmacokinetics and pharmacodynamics of insulin human and insulin lispro are similar following IV administration in healthy individuals; however, the safety and efficacy of IV insulin lispro have not been evaluated in clinical trials in patients with diabetes mellitus.1,51,74 Following single IV doses of 0.1-0.2 units/kg, the absolute bioavailabilities of insulin lispro and insulin human were similar, ranging from 55-77%.1,145

The onset of glycemic response following subcutaneous injection of insulin lispro in healthy individuals or in patients with type 1 or 2 diabetes mellitus generally ranges from 0.25-0.5 hours versus 0.5-1 hours for insulin human; 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 subcutaneous administration in these individuals or patients, 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 Many factors can affect the onset, degree, and duration of insulin activity, including 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 After subcutaneous administration, onset of action of insulin lispro from abdominal, deltoid, and thigh sites is similar, and variations in absorption related to site of administration are smaller than those observed with regular insulin.1,11,12,51,74,83,145 However, 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

Distribution

The volume of distribution of insulin lispro reportedly is identical to that of insulin human and ranges from 0.26-0.36 L/kg.1,165,173 Distribution of insulin lispro when given in the fixed-combination formulation containing protamine sulfate (Humalog^® Mix75/25^®) has not been determined.165,173 It is not known whether insulin lispro is distributed into human milk; however, other insulins (e.g., insulin human) are distributed into milk.1 In a study in a limited number of pregnant women with gestational diabetes, the drug did not appear to cross the placenta.164

Elimination

In healthy adults, the half-life of subcutaneously administered insulin lispro or insulin human is 1 or 1.5 hours, respectively, while systemic clearance of insulin lispro and insulin human is similar.2,51 Following IV administration, insulin lispro and insulin human reportedly exhibit identical dose-dependent elimination, with half-lives of 26 or 52 minutes at doses of 0.1 or 0.2 units/kg, respectively.1,51

The metabolic fate of insulin lispro alone or in fixed combination with insulin lispro protamine has not been determined in humans; however, in animals, metabolism of insulin lispro is identical to that of insulin human.1,165

Some studies with insulin human have shown increased circulating insulin concentrations in patients with renal or hepatic failure; information on the use of insulin lispro in such patients is limited.1 In a study in a limited number of patients with type 2 diabetes mellitus and various degrees of renal function, sensitivity to insulin lispro increased as renal function declined.173 (See Cautions: Precautions and Contraindications and see Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Chemistry and Stability

Chemistry

Insulin lispro is a biosynthetic human insulin analog that is structurally identical to insulin human except for reversal of the sequence of lysine and proline on the B chain of the molecule; in insulin lispro, lysine and proline occur at positions 28 and 29, respectively, of the B chain.1,2,8,13,51,145 The inversion of lysine and proline in the amino acid sequence eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of dimer subunits composing the hexameric form of insulin lispro.2,8,12,13,18,74,145 Endogenous insulin is stored in the pancreas as a stable, zinc-containing hexamer; stabilization of insulin lispro in the commercial formulation is accomplished by addition of zinc and m -cresol.1,2,8,51,145 The hexamers formed with zinc and insulin lispro are weak compared with those of human insulin and dissociate rapidly into monomers of the insulin analog that are absorbed through vascular endothelial cells.2,8,12,51,73,145 Consequently, insulin lispro has a more rapid onset of action than insulin human when given subcutaneously while retaining the conformation of critical sites necessary for binding to and activating the insulin receptor.2,8,12,13,14,18,51,145

Biosynthetic insulin lispro (Humalog^®) is prepared using recombinant DNA technology and special laboratory strains of nonpathogenic E. coli .1,51,145 The E. coli bacteria have been genetically modified by the addition of plasmids that incorporate genes for the lispro form of human proinsulin.1,4,81,144,145

Commercially available biosynthetic insulin lispro injection consists of zinc insulin lispro crystals that are prepared by precipitating insulin lispro in the presence of zinc oxide and dissolving the crystals in water for injection, resulting in a clear aqueous solution.1,51 Each mL contains 100 USP units of biosynthetic insulin lispro solution and 19.7 mcg of zinc.1 Each mL of insulin lispro also contains dibasic sodium phosphate 1.88 mg, glycerin 16 mg, m -cresol 3.15 mg, and trace amounts of phenol.1 Sodium hydroxide and/or hydrochloric acid may be added during manufacture of biosynthetic insulin lispro zinc injection to adjust pH to 7-7.8.1,145

Insulin lispro also is commercially available in fixed combination with insulin lispro protamine (neutral protamine lispro [NPL]), an intermediate-acting insulin.159,160,165 Insulin lispro protamine is prepared by crystallizing insulin lispro with protamine sulfate to produce a suspension with similar pharmacokinetics as isophane (NPH) insulin human.159,161,165 Each mL of the fixed combination of insulin lispro and insulin lispro protamine suspension (Humalog^® Mix75/25^®) contains 100 USP units of insulin lispro, 25 mcg of zinc (as zinc oxide), and 0.28 mg of protamine sulfate.165 Each mL of Humalog^® Mix75/25^® also contains dibasic sodium phosphate 3.78 mg, glycerin 16 mg, cresol 1.76 mg, and phenol 0.715 mg.165 Sodium hydroxide and/or hydrochloric acid may be added during manufacture of Humalog^® Mix75/25^® or Humalog^® Mix50/50^® injection to adjust pH to 7-7.8.165,173 Each mL of Humalog^® Mix50/50^® contains 100 units of insulin lispro, 0.03 mg of zinc ion (as zinc oxide), and 0.19 mg of protamine sulfate.173 Each mL of Humalog^® Mix50/50^® also contains dibasic sodium phosphate 3.78 mg, glycerin 16 mg, m-cresol 2.2 mg, and phenol 0.89 mg.173

Stability

Insulin lispro injection should be dispensed in the original, unopened, multiple-dose vial, disposable injection pen, or injection cartridge supplied by the manufacturer.1,51,155 When stored as directed, the vials and cartridges have an expiration date of not later than 2 years after the date of manufacture.1,51,145 Unopened vials or disposable injection pens of insulin lispro alone or in fixed combination with insulin lispro protamine or cartridges of the drug that have not been placed in a delivery device should be stored at 2-8°C and should not be subjected to freezing; the drug vial or cartridge should be discarded if it is frozen.1,19,155,156,160,165,171,172,173,174 Vials or cartridges of insulin lispro that cannot be refrigerated or vials and disposable injection pens that are in use may be stored at room temperature not exceeding 30°C for up to 28 days;1,19,51,81,155,171,172 exposure to extremes in temperature or direct sunlight should be avoided.1,155,165,171,172 Disposable injection pens of insulin lispro in fixed combination with insulin lispro protamine (Humalog^® Mix75/25^® Pen, Humalog^® Mix50/50^® Pen) that are in use may be stored at room temperature (below 30°C) for up to 10 days; exposure to extremely hot temperatures or direct light should be avoided.160,165,173,174 The manufacturer states that, once assembled by placement in the injectable pen (Owen Mumford Autopen^®), insulin lispro cartridges and the injection device should be stored at room temperature and should not be refrigerated nor exposed to extremely hot temperatures or direct sunlight.1,51,171 Any unused insulin lispro in unrefrigerated vials, disposable injection pens, or cartridges should be discarded after 28 days.1,19,51,145,155,156 With the fixed combination of insulin lispro and insulin lispro protamine in disposable injection pens (Humalog^® Mix75/25^® Pen, Humalog^® Mix50/50^® Pen) or in vials, any unused portion should be discarded after 10 or 28 days, respectively.160,165,173,174

When insulin lispro is diluted with the sterile diluent supplied by the manufacturer for improved accuracy in preparing pediatric dosages (see Dosage and Administration: Administration), the diluted solution should be discarded after 28 days when stored at 5°C or after 14 days when stored at 30°C.165

Insulin lispro injection should be inspected visually prior to administration whenever the solution and the container permit.1,19 If the solution exhibits discoloration, turbidity, or unusual viscosity, the vial or cartridge should be discarded,1 since these changes indicate deterioration or contamination.19 Insulin lispro in fixed combination with insulin lispro protamine should be not be used if resuspension cannot be achieved (suspension should appear uniformly cloudy).173,174 (See Dosage and Administration: Administration.)Patients observing unexplained increases in blood glucose concentrations during insulin therapy should be particularly vigilant for any indications of loss of insulin potency and should contact a clinician if insulin requirements change markedly.19,174

The compatibility of insulin lispro injection with other drugs depends on several factors (e.g., pH of the injection, concentration of the drugs, specific diluents used, temperature, resulting pH); specialized references should be consulted for specific compatibility information.19,84,85 For convenience, insulin lispro has been administered with a longer-acting insulin (e.g., isophane [NPH] insulin human) in the same syringe.1,51,73,74,121 Mixing of insulin lispro with other insulins may be associated with physicochemical changes that could alter the physiologic response to the insulins.1,19,28,51,73,74,121 When insulin lispro (Humalog^®) was mixed with isophane (NPH) insulin human (Humulin N^®), binding of insulin lispro with stabilizers/excipients (e.g., zinc, protamine) in the NPH insulin decreased the absorption rate and the peak concentration, but not the total bioavailability, of insulin lispro.1,51,73,79 (See Dosage and Administration: Administration.) Mixtures of insulin lispro and a longer-acting insulin (e.g., NPH insulin human should be given within 5 minutes after mixing; insulin mixtures should not be given IV.1 The manufacturer states that the effect of mixing Humalog^® with insulins of animal origin (no longer commercially available in the US) or human insulins produced by other manufacturers has not been studied.1 Whenever 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

When insulin lispro is administered via an external subcutaneous controlled-infusion device (pump), the drug should not be diluted or mixed with any other insulin.1 Insulin lispro in the external infusion device should not be exposed to temperatures exceeding 37°C during administration.1,171 Infusions sets (reservoir syringe, tubing, and catheter), the Disetronic^® D-TRON^® or Disetronic^® D-TRON^®plus cartridge adapter, and insulin lispro in the pump reservoir should be replaced and a new infusion site selected at least every 48 hours.1 The 3-mL cartridges used in the Disetronic^® D-TRON^® or Disetronic^® D-TRON^®plus insulin pumps should be discarded after 7 days, even if some drug remains in the reservoir.1,171

Simulated administration of insulin lispro by continuous subcutaneous 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 insulin lispro 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

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