Insulin Lispro (Systemic)


VA CLASSIFICATION
Primary: HS501

Commonly used brand name(s): Humalog.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidiabetic agent{01}

Indications

Accepted

Diabetes mellitus (treatment adjunct)—Insulin lispro is indicated in the treatment of diabetes mellitus for the control of hyperglycemia.{01}{03}{04} Insulin lispro has a more rapid onset and shorter duration of action than regular human insulin and, therefore, in patients with type 1 diabetes, insulin lispro should be used in a regimen that includes a longer acting insulin. {01}{03} In patients with type 2 diabetes, insulin lispro may be used without a longer acting insulin when it is used in combination with a sulfonylurea agent.1{03}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Analog of human insulin created by reversing amino acids at positions 28 (proline) and 29 (lysine) on the B-chain. {01} Synthesized by recombinant DNA process involving genetically engineered Escherichia coli . {01} {02}
Molecular weight—
    5808 {01}


pH
    7 to 7.8. {01}

Mechanism of action/Effect:

Like other types of insulin, the primary activity of insulin lispro is to control the metabolism of glucose. {01} Also, like other types of insulin, insulin lispro acts in muscle and other tissues (except the brain) to increase intracellular transport of glucose and amino acids, promote anabolism, and inhibit protein catabolism. In the liver, insulin lispro promotes conversion of glucose to glycogen or fat, and inhibits gluconeogenesis. {01}

Absorption:

The rate of absorption of insulin lispro demonstrates inter- and intraindividual variability and is dependent upon many factors, including the site of injection; temperature of, and blood flow to, the site; and exercise. {01} Insulin lispro was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 USP Insulin Human Units of regular human insulin or insulin lispro at abdominal, deltoid, or femoral sites. {01} Following abdominal administration of insulin lispro, serum drug concentrations were higher and the duration of action slightly shorter than following deltoid or femoral administration. {01}

Bioavailability ranges from 55 to 77% following doses of 0.1 to 0.2 USP Insulin Human Units per kg of body weight. {01}

Distribution:

The volume of distribution ranges from 0.26 to 0.36 L per kg. {01}

Biotransformation:

Studies have not been done in humans. {01} However, studies in animals indicate that the metabolism of insulin lispro is identical to that of regular human insulin. {01}

Half-life:


Elimination:

Intravenous: 26 and 52 minutes following doses of 0.1 and 0.2 USP Insulin Human Units, respectively (identical to that of regular human insulin). {01}

Subcutaneous: 1 hour (versus 1.5 hours for regular human insulin). {01}


Onset of action:

Studies in healthy volunteers and patients with diabetes have shown that insulin lispro has a more rapid onset of action than regular human insulin. {01}

Time to peak serum concentration

30 to 90 minutes following subcutaneous doses ranging from 0.1 to 0.4 USP Insulin Human Units per kg of body weight to healthy volunteers. {01} Similar results were seen in patients with type 1 diabetes. {01}

Time to peak effect:

Studies in healthy volunteers and patients with diabetes have shown that insulin lispro has an earlier time to peak effect than regular human insulin. {01}

Duration of action:

Studies in healthy volunteers and patients with diabetes have shown that insulin lispro has a shorter duration of action than regular human insulin. {01}


Precautions to Consider

Cross-sensitivity and/or related problems

Production of antibodies cross-reactive to human insulin and insulin lispro was observed in patients participating in large clinical trials. During the 12-month trials, the largest increase in antibody concentration to human insulin and insulin lispro was seen in patients new to insulin therapy. {01}

Carcinogenicity

Long-term studies to evaluate the carcinogenic potential of insulin lispro have not been done in animals. {01}

Mutagenicity

No evidence of mutagenicity was found in a series of in vitro and in vivo studies, including bacterial mutation tests, unscheduled DNA synthesis, mouse lymphoma assay, chromosomal aberration tests, and a micronucleus test. {01}

Pregnancy/Reproduction
Fertility—
No evidence of impaired fertility was found in animal studies. {01}

Pregnancy—
Studies have not been done in humans. {01} However, women with diabetes must be educated about the necessity of maintaining glycemic control before conception and during pregnancy to improve fetal outcome. Insulin requirements often are decreased during the first trimester and increased during the second and third trimesters. {01}

Studies in pregnant rats and rabbits given doses 4 and 0.3 times, respectively, the average human dose of 40 units per day based on body surface area have not shown that insulin lispro causes adverse effects in the fetus. {01}

FDA Pregnancy Category B. {01}

Breast-feeding

It is not known whether insulin lispro is distributed into breast milk. {01} Women who are breast-feeding may require adjustments in their dosages of insulin lispro, in their meal plans, or in both. {01}

Pediatrics

Studies performed in patients 3 years of age or older have not demonstrated pediatrics-specific problems that would limit the usefulness of insulin lispro in children{03}.


Geriatrics


Studies performed in 338 patients 65 years of age or older (the majority of whom had type 2 diabetes) have not demonstrated geriatrics-specific problems that would limit the usefulness of insulin lispro in the elderly.{03}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Antidiabetic agents, oral{01}{02}    (concurrent use may necessitate a decrease in insulin lispro dosage {01} {02})


Hyperglycemia-causing agents, such as:
Corticosteroids{01}{02}
Estrogens{01}
Isoniazid{01}
Niacin{01}
Oral contraceptives{01}{02}
Phenothiazines{01}
Thyroid hormones{01}{02}    (these medications may cause loss of glycemic control; insulin requirements may be increased {01} {02})


Hypoglycemia-causing agents, such as:
Alcohol{01}{02}
Angiotensin-converting enzyme (ACE) inhibitors{01}
Monoamine oxidase (MAO) inhibitors,{01} including furazolidone, procarbazine, and selegiline
Octreotide{01}
Salicylates{01}{02}
Sulfonamides{01}{02}    (these medications may change metabolic control of glucose concentrations; insulin requirements may be decreased {01} {02})


» Sympatholytics, such as beta-adrenergic blocking agents{01}{02}    (sympatholytics may mask some of the symptoms of developing hypoglycemia, making detection of this condition more difficult {01} {02})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypoglycemia{01}
Risk-benefit should be considered when the following medical problems exist
» Diarrhea{02} or
» Vomiting{02}    (may precipitate hypoglycemia; adjustment of insulin and/or insulin lispro dosage may be required {02})


» Fever or
» Infection{02}    (may precipitate hyperglycemia; adjustment of insulin and/or insulin lispro dosage may be required {02})


Hepatic function impairment{01} or
Renal function impairment{01}    (studies have shown increased concentrations of circulating insulin in patients with hepatic or renal function impairment; {01} careful glucose monitoring and adjustment of insulin lispro dosage may be necessary {01})


Hypersensitivity to insulin lispro{01}
» Hypoglycemia-causing conditions, such as:
Adrenal insufficiency{02}
Pituitary insufficiency{02}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Glucose concentrations, blood{01}{02} and/or urine{02}    (monitoring essential as a guide to therapeutic efficacy {01})


» Glycosylated hemoglobin (hemoglobin A 1c) determinations{01}    (periodic monitoring recommended to assess long-term glycemic control {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypoglycemia {01}{02}(anxiety ; behavior change similar to drunkenness; blurred vision; cold sweats; coma; confusion; depression; difficulty in concentrating; dizziness or lightheadedness; drowsiness; excessive hunger; fast heartbeat; headache; irritability or abnormal behavior; nervousness; nightmares ; restless sleep; seizures; shakiness; slurred speech; tingling in the hands, feet, lips, or tongue)

Note: In patients with type 1 diabetes, the risk of nocturnal hypoglycemia is less with insulin lispro than with regular human insulin. {03}{04}


Incidence less frequent or rare
    
Allergy, local (itching, redness, or swelling at injection site ){01}{02}
    
allergy, systemic (decrease in blood pressure; rapid pulse; shortness of breath ; skin rash or itching over the entire body; sweating; wheezing)— may be life-threatening{01}{02}
    
hypokalemia (dryness of mouth ; increased thirst; irregular heartbeat ; mood or mental changes; muscle cramps or pain; nausea or vomiting; unusual tiredness or weakness; weak pulse){01}
    
lipoatrophy at injection site ( depression of the skin at injection site){01}{02}
    
lipohypertrophy at injection site (thickening of the skin at injection site){02}

Note: Local allergic reactions are usually minor and resolve within a few days to a few weeks. {01} {02} In some cases, the reactions may be related to irritants in a skin cleansing agent or poor injection technique rather than to the medication. {01} {02}






Overdose
For specific information on the agent used in the management of insulin lispro overdose, see the Glucagon (Systemic) monograph.

For more information on the management of overdose, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms— in parentheses where appropriate)not necessarily inclusive:
    
Hypoglycemia ( anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; coma ; confusion; depression; difficulty in concentrating; dizziness or lightheadedness ; drowsiness; excessive hunger; fast heartbeat; headache; irritability or abnormal behavior; nervousness; nightmares ; restless sleep; seizures; shakiness; slurred speech; tingling in the hands, feet, lips, or tongue){01}


Treatment of overdose


Specific treatment:
Mild hypoglycemia without neurologic symptoms or loss of consciousness should be treated with immediate ingestion of glucose and adjustments to medication dosage and/or meal plan. {01}

Severe hypoglycemia including coma, seizures, or other neurologic impairment requires immediate emergency medical assistance. {01} The patient should immediately be given intramuscular or subcutaneous glucagon, or intravenous glucose, and observed because relapse may occur following apparent clinical recovery. {01}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Insulin Lispro (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to insulin lispro

Pregnancy—Importance of maintaining glycemic control to improve fetal outcome; insulin requirements may change during pregnancy





Breast-feeding—Women who are breast-feeding may require adjustments in their dosages of insulin lispro, in their meal plans, or in both
Other medications, especially sympatholytics
Other medical problems, especially adrenal insufficiency; diarrhea; fever; hypoglycemia; infection; pituitary insufficiency; or vomiting

Proper use of this medication
» Carefully reading patient instruction sheet contained in insulin lispro package {02} and understanding:

• How to prepare the medication


• How to inject the medication


• How to dispose of syringes, needles, and injection devices


» Carefully selecting and rotating injection sites, following health care professional"s recommendations {02}

» Taking insulin lispro within 15 minutes before the meal when used as a mealtime insulin

» Adhering to recommended regimens for diet, exercise, and glucose monitoring

» Proper dosing

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress, especially during the first few weeks of treatment
»
Carefully following special instructions of health care team
Discussing use of alcohol {02}

Not taking other medications unless discussed with physician {02}

Getting counseling for family members to help the patient with diabetes; also, special counseling for pregnancy planning and contraception {02}

Discussing travel arrangements, including transporting insulin lispro, carrying medical history and extra supplies of insulin lispro and syringes or injection devices, and adjusting dosage if traveling across more than two time zones {02}
» Preparing for and knowing what to do in case of an emergency by carrying medical history and current medication list, wearing medical identification, keeping extra needed medical supplies and quick-acting sugar, and having nonexpired glucagon kit and needles nearby {02}

» Recognizing what brings on symptoms of hypoglycemia, such as using other antidiabetic medication; delaying or missing a meal or snack; exercising more than usual; drinking significant amounts of alcohol; or sickness, such as vomiting or diarrhea {02}

» Recognizing symptoms of hypoglycemia: anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; depression; difficulty in concentrating; dizziness or lightheadedness; drowsiness; excessive hunger; fast heartbeat; headache; irritability or abnormal behavior; nervousness; nightmares; restless sleep; shakiness; slurred speech; and tingling in the hands, feet, lips, or tongue {02}

» Knowing what to do if symptoms of hypoglycemia occur, such as eating glucose tablets or gel, corn syrup, honey, or sugar cubes; drinking fruit juice, nondiet soft drink, or sugar dissolved in water; or injecting glucagon if symptoms are severe {02}

» Recognizing what brings on symptoms of hyperglycemia, such as not taking enough or skipping a dose of insulin lispro or insulin; overeating or not following meal plan; having a fever or infection; or exercising less than usual {02}

» Recognizing symptoms of hyperglycemia and ketoacidosis: blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination (frequency and volume); ketones in urine; loss of appetite; stomachache, nausea, or vomiting; tiredness; troubled breathing (rapid and deep); unconsciousness; and unusual thirst

» Knowing what to do if symptoms of hyperglycemia occur, such as checking blood glucose and contacting a member of the health care team {02}


Side/adverse effects
Signs of potential side effects, especially hypoglycemia, local allergy, systemic allergy, hypokalemia, and lipoatrophy or lipohypertrophy at injection site


General Dosing Information
The glucose-lowering capability of one unit of insulin lispro is equal to that of one unit of regular human insulin{01}{04}. However, patients taking insulin lispro may require a change in dosage from that used with other insulins. If an adjustment is needed, it may occur with the first dose or over a period of several weeks{04}.

Because of the short duration of action of insulin lispro, supplementation with a longer acting insulin may be required to maintain glycemic control, especially in patients with type 1 diabetes. {01} {02}{03} However, in patients with type 2 diabetes, insulin lispro may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents{03}.

Insulin lispro 3 times a day before meals plus sulfonylureas improved glycosylated hemoglobin (HbA1C) concentrations to a greater extent than did insulin lispro 3 times a day plus human isophane insulin (NPH insulin) at bedtime or NPH insulin at bedtime plus sulfonylureas.{03}

Changes in insulin strength, type (e.g., analog, NPH, regular), source (beef and pork, human, pork), method of manufacture (naturally occurring, recombinant DNA process), or manufacturer should be made cautiously and only under medical supervision. {01} {02}{04} A change in any of these parameters may require an adjustment of insulin dosage. {01}{04} Adjustment of insulin dosage also may be necessary following a change in meal plan or amount of exercise, or following an acute illness, emotional disturbance, or period of stress. {01}

Different types of insulin are sometimes mixed in the same syringe to achieve a more accurate matching of insulin availability to the patient"s requirements in a single dose. If insulin lispro is to be mixed, several factors should be considered:    • Physicochemical changes in the mixture may occur (immediately or over time), resulting in a physiological response to the mixture that differs from the response to the individual insulin preparations. {01}No decrease in absorption rate or in total bioavailability was seen when insulin lispro was mixed with human isophane insulin (NPH insulin) or with human extended insulin zinc suspension (ultralente insulin). {03}
   • When insulin lispro is mixed with longer acting insulins, the mixture should be administered within 15 minutes before a meal. {01}{04}
   • When it is mixed with a longer acting insulin, insulin lispro should be drawn into the syringe first to prevent clouding by the longer acting insulin. {01} {02} The mixture should be used immediately and should not be administered intravenously. {01}
   • The effects of mixing insulin lispro with insulins of animal source or other manufacturers have not been studied. {01}



Parenteral Dosage Forms

INSULIN LISPRO INJECTION

Usual adult and adolescent dose
Antidiabetic agent
Subcutaneous, dosage must be determined by the physician based on the patient"s metabolic needs, eating habits, and other lifestyle variables. {01}{03}{04}


Note: When used as a mealtime insulin, insulin lispro should be administered within fifteen minutes before the meal{01} {02}{03}{04} or immediately after the meal. {03}


Usual pediatric dose
See Usual adult and adolescent dose.

Note: To improve accuracy of dosing in pediatric patients, a diluent may be used{01}. See Preparation of dosage form.
When used as a mealtime insulin, insulin lispro should be administered within fifteen minutes before the meal or immediately after the meal. {03}


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


100 USP Insulin Human Units per mL (Rx) [Humalog (glycerin 16 mg) (dibasic sodium phosphate 1.88 mg) (m-cresol 3.15 mg) (zinc oxide content adjusted to provide 0.0197 mg zinc ion) (phenol trace) ( water for injection){01}]

Note: Insulin lispro is available in 10-mL vials, 1.5-mL cartridges, 3-mL cartridges, and 3–mL disposable insulin delivery devices. The 1.5-mLcartridges may be used with any of the following insulin delivery devices: Becton Dickinson and Company's B-D® Pen or Novo NordiskA/S's NovoPen®, NovolinPen®, or NovoPen® 1.5. {02}{03}The 3-mL cartridges are for use in the Owen Mumford, Ltd.'s Autopen® 3 mL insulin delivery device.{05}


Canada—


100 USP Insulin Human Units per mL (Rx) [Humalog (glycerin 16 mg) (dibasic sodium phosphate 1.88 mg) (m-cresol 3.15 mg) (zinc ion 0.0197 mg){04}]

Note: Insulin lispro is available in 10–mL vials, 1.5 and 3–mL cartridges, and 3–mL disposable insulin delivery devices{04}.


Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). {01} Protect from freezing. {01} {02} If refrigeration is not possible, insulin lispro may be stored unrefrigerated, at temperatures not exceeding 30 °C (86 °F) and protected from direct light, for up to 28 days. {01} {02}Following insertion into a pen, the cartridge and pen should not be refrigerated{04}.

Preparation of dosage form:
Insulin lispro (Humalog® ) may be diluted with Sterile Diluent for Humalog® , Humulin® N, Humulin® 50/50, Humulin® 70/30, and NPH Iletin® to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50){03}.

Stability:
Diluted insulin lispro can be used up to 28 days when stored at 5 °C (41 °F) or for 14 days when stored at 30 °C (86 °F){03}.

Auxiliary labeling:
   • Refrigerate.
   • Do not freeze.



Revised: 05/02/2001



References
  1. Humalog package insert (Eli Lilly—US), Rev 07/30/97, Rec 02/20/98.
  1. Humalog patient package insert (Eli Lilly—US), Rev 06/30/97, Rec 02/20/98.
  1. Product Information: Humalog®, insulin lispro injection (rDNA origin). Eli Lilly, Indianapolis, IN, (PI revised 4/2000), reviewed 5/2000.
  1. Product Information: Humalog®, insulin lispro injection. Eli Lilly Canada, Scarborough, Ontario, CAN (PI revised 11/1999) reviewed 6/2000.
  1. Product Information: Humalog®, insulin lispro injection (rDNA origin). Eli Lilly, Indianapolis, IN, (PI revised 5/2000), reviewed 4/2001.
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