Insulin lispro
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]
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Overview
Insulin lispro is an insulin analog that is FDA approved for the {{{indicationType}}} of improve glycemic control in adults and children with diabetes mellitus. Common adverse reactions include injection site reaction, hypoglycemia, hypokalemia, lipodystrophy.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Dosage Considerations
- When given subcutaneously, insulin lispro has a more rapid onset of action and a shorter duration of action than regular human insulin.
- The dosage of insulin lispro must be individualized. Blood glucose monitoring is essential in all patients receiving insulin therapy.
- The total daily insulin requirement may vary and is usually between 0.5 to 1 unit/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Subcutaneous Administration
- Insulin lispro should be given within 15 minutes before a meal or immediately after a meal.
- Insulin lispro given by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.
- Insulin lispro administered by subcutaneous injection should be given in the abdominal wall, thigh, upper arm, or buttocks. Injection sites should be rotated within the same region (abdomen, thigh, upper arm, or buttocks) from one injection to the next to reduce the risk of lipodystrophy.
Continuous Subcutaneous Infusion (Insulin Pump)
- Insulin lispro may be administered by continuous subcutaneous infusion by an external insulin pump. Do not use diluted or mixed insulins in external insulin pumps. Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy. Change the insulin lispro in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days.
- The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen. Although there is significant variability among patients, approximately 50% of the total dose is usually given as meal-related boluses of insulin lispro and the remainder is given as a basal infusion. Insulin lispro is recommended for use in pump systems suitable for insulin infusion such as MiniMed, Disetronic, and other equivalent pumps.
Intravenous Administration
- Insulin lispro can be administered intravenously under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia. Insulin lispro should be used at concentrations from 0.1 unit/mL to 1.0 unit/mL in infusion systems containing 0.9% sodium chloride.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
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Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
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Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
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Contraindications
Insulin lispro is contraindicated:
- During episodes of hypoglycemia
- In patients who are hypersensitive to insulin lispro or to any of its excipients.
Warnings
Dose Adjustment and Monitoring
- Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
- As with all insulin preparations, the time course of action for insulin lispro may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages.
Hypoglycemia
- Hypoglycemia is the most common adverse effect associated with insulins, including insulin lispro. The risk of hypoglycemia increases with tighter glycemic control. Patients must be educated to recognize and manage hypoglycemia. Hypoglycemia can happen suddenly and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening or cause death.
- The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia.
- As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery.
- Rapid changes in serum glucose levels may induce symptoms similar to hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient's awareness of hypoglycemia.
Hypersensitivity and Allergic Reactions
- Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including insulin lispro.
Hypokalemia
- All insulin products, including insulin lispro, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations and patients receiving intravenously administered insulin).
Renal or Hepatic Impairment
- Frequent glucose monitoring and insulin dose reduction may be required in patients with renal or hepatic impairment.
Mixing of Insulins
- Insulin lispro for subcutaneous injection should not be mixed with insulin preparations other than NPH insulin. If insulin lispro is mixed with NPH insulin, insulin lispro should be drawn into the syringe first. Injection should occur immediately after mixing.
- Do not mix insulin lispro with other insulins for use in an external subcutaneous infusion pump.
Subcutaneous Insulin Infusion Pumps
- When used in an external insulin pump for subcutaneous infusion, insulin lispro should not be diluted or mixed with any other insulin. Change the insulin lispro in the reservoir at least every 7 days, change the infusion sets and the infusion set insertion site at least every 3 days. Insulin lispro should not be exposed to temperatures greater than 98.6°F (37°C).
- Malfunction of the insulin pump or infusion set or insulin degradation can rapidly lead to hyperglycemia and ketosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with insulin lispro may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.
Drug Interactions
- Some medications may alter insulin requirements and the risk for hypoglycemia or hyperglycemia.
Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists
- Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including , and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.
- The frequencies of Treatment-Emergent Adverse Events during insulin lispro clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.
Insulin initiation and intensification of glucose control
- Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and peripheral neuropathy.
Lipodystrophy
- Long-term use of insulin, including insulin lispro, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy.
Weight gain
- Weight gain can occur with insulin therapy, including insulin lispro, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.
Peripheral Edema
- Insulin, including insulin lispro, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.
- Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)
- In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for insulin lispro and regular human insulin treated patients (see Table 3).
- In a randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions were similar for insulin lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction.
Allergic Reactions
- Local Allergy: As with any insulin therapy, patients taking insulin lispro may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of insulin lispro. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.
- Systemic Allergy: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including insulin lispro. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.
- In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving insulin lispro (n=2944).
- Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in insulin lispro.
Antibody Production
- In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and insulin lispro (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.
Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of insulin lispro. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Medication errors in which other insulins have been accidentally substituted for insulin lispro have been identified during postapproval use.
Drug Interactions
A number of drugs affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring. Following are some of the examples:
- Drugs That May Increase the Blood-Glucose-Lowering Effect of Insulin Lispro and Susceptibility to Hypoglycemia: Oral antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, pramlintide, disopyramide, fibrates, propoxyphene, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide).
- Drugs That May Reduce the Blood-Glucose-Lowering Effect of Insulin Lispro: Corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones.
- Drugs That May Increase or Reduce the Blood-Glucose-Lowering Effect of Insulin Lispro: Beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
- Drugs That May Reduce the Signs of Hypoglycemia: Beta-blockers, clonidine, guanethidine, and reserpine.
Use in Specific Populations
Pregnancy
- All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking insulin lispro.
- Although there are limited clinical studies of the use of insulin lispro in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome.
- In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.
- In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.24 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Insulin lispro in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Insulin lispro during labor and delivery.
Nursing Mothers
It is unknown whether insulin lispro is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when insulin lispro is administered to a nursing woman. Use of insulin lispro is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.
Pediatric Use
- Insulin lispro is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. Insulin lispro has not been studied in pediatric patients younger than 3 years of age. insulin lispro has not been studied in pediatric patients with type 2 diabetes.
- As in adults, the dosage of insulin lispro must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose.
Geriatic Use
Of the total number of subjects (n=2834) in eight clinical studies of insulin lispro, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of insulin lispro action have not been performed.
Gender
There is no FDA guidance on the use of Insulin lispro with respect to specific gender populations.
Race
There is no FDA guidance on the use of Insulin lispro with respect to specific racial populations.
Renal Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.
Hepatic Impairment
Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Insulin lispro in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Insulin lispro in patients who are immunocompromised.
Administration and Monitoring
Administration
- Subcutaneous Administration (single dose)
- Continuous Subcutaneous Infusion (Insulin Pump)
- Intravenous Administration
Monitoring
- Glucose monitoring is essential for patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose. Concomitant oral antidiabetic treatment may need to be adjusted.
- As with all insulin preparations, the time course of action for insulin lispro may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, or local temperature. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages.
IV Compatibility
Solution
Compatible
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Not Tested
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Variable
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Incompatible
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Y-Site
Compatible
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Variable
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Incompatible
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Admixture
Compatible
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Variable
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Incompatible
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Syringe
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TPN/TNA
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Incompatible
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Overdosage
Acute Overdose
Signs and Symptoms
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Management
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Chronic Overdose
Signs and Symptoms
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Management
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Pharmacology
Insulin lispro
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| ATC code | A10 |
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| Formula | Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox |
| Mol. mass | 5813.63 g/mol |
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| Bioavailability | ? |
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Mechanism of Action
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Clinical Studies
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How Supplied
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Storage
There is limited information regarding Insulin lispro Storage in the drug label.
Images
Drug Images
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Patient Counseling Information
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Precautions with Alcohol
Alcohol-Insulin lispro interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Insulin lispro Brand Names in the drug label.
Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
Drug Shortage Status
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References
The contents of this FDA label are provided by the National Library of Medicine.