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Insulin Preparations


Pronunciation

 (IN su lin prep a RAY shuns)


U.S. Brand Names

 Apidra™; Humalog®; Humalog® Mix 75/25™; Humulin® 50/50; Humulin® 70/30; Humulin® L; Humulin® N; Humulin® R; Humulin® R (Concentrated) U-500; Humulin® U; Lantus®; Lente® Iletin® II [DSC]; Novolin® 70/30; Novolin® L [DSC]; Novolin® N; Novolin® R; NovoLog®; NovoLog® Mix 70/30; NPH Iletin® II; Regular Iletin® II; Velosulin® BR (Buffered) [DSC]


Synonyms

 Aspart, Insulin; Glargine, Insulin; Glulisine, Insulin; Lente, Insulin; Lispro, Insulin; NPH, Insulin; Regular, Insulin


Generic Available

 No


Canadian Brand Names

 Humalog®; Humalog® Mix 25™; Humulin®; Iletin® II Pork; Novolin® ge; NovoRapid®


Use

 Treatment of type 1 diabetes mellitus (insulin dependent, IDDM); type 2 diabetes mellitus (noninsulin dependent, NIDDM) unresponsive to treatment with diet and/or oral hypoglycemics; adjunct to parenteral nutrition


Use - Unlabeled/Investigational

 Hyperkalemia (regular insulin only; use with glucose to shift potassium into cells to lower serum potassium levels)


Pregnancy Risk Factor

 B; C (insulin glargine [Lantus®]; insulin aspart [NovoLog®])


Pregnancy Implications

 Does not cross the placenta. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.


Lactation

 Does not enter breast milk/compatible


Contraindications

 Hypersensitivity to any component of the formulation


Warnings/Precautions

 Hypoglycemia is the most common adverse effect of insulin. The timing of hypoglycemia differs among various insulin formulations. Any change of insulin should be made cautiously; changing manufacturers, type and/or method of manufacture, may result in the need for a change of dosage; human insulin differs from animal-source insulin; regular insulin is the only insulin to be used I.V.; hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (insulin glargine, Ultralente®, insulin U) may delay recovery from hypoglycemia; use with caution in renal or hepatic impairment

In type 1 diabetes mellitus (insulin dependent, IDDM), insulin lispro (Humalog®) and insulin glulisine (Apidra™) should be used in combination with a long-acting insulin. However, in type 2 diabetes mellitus (noninsulin dependent, NIDDM), insulin lispro (Humalog®) may be used without a long-acting insulin when used in combination with a sulfonylurea.

Insulin aspart (Apidra™, NovoLog®, NovoLog® Mix 70/30): Safety and efficacy of use in children have not been established


Adverse Reactions

 Frequency not defined.

Cardiovascular: Palpitation, tachycardia, pallor

Central nervous system: Fatigue, mental confusion, loss of consciousness, headache, hypothermia

Dermatologic: Urticaria, redness

Endocrine & metabolic: Hypoglycemia

Gastrointestinal: Hunger, nausea, numbness of mouth

Local: Itching, edema, stinging, pain or warmth at injection site; atrophy or hypertrophy of SubQ fat tissue

Neuromuscular & skeletal: Muscle weakness, paresthesia, tremor

Ocular: Transient presbyopia or blurred vision

Miscellaneous: Diaphoresis, anaphylaxis, local allergy, systemic allergic symptoms


Overdosage/Toxicology

 Symptoms of overdose include tachycardia, anxiety, hunger, tremor, pallor, headache, motor dysfunction, speech disturbances, sweating, palpitations, coma, and death. Antidote is glucose and glucagon, if necessary.


Drug Interactions

 Induces CYP1A2 (weak)

Drugs which DECREASE hypoglycemic effect of insulin:

Contraceptives (oral), corticosteroids, dextrothyroxine, diltiazem, dobutamine, epinephrine, niacin, smoking, thiazide diuretics, thyroid hormone

Drugs which INCREASE hypoglycemic effect of insulin:

Alcohol, alpha-blockers, anabolic steroids, beta-blockers*, clofibrate, fenfluramine, guanethidine, MAO inhibitors, pentamidine, phenylbutazone, salicylates, sulfinpyrazone, tetracyclines

*Nonselective beta-blockers may delay recovery from hypoglycemic episodes and mask signs/symptoms of hypoglycemia. Cardioselective agents may be alternatives.


Ethanol/Nutrition/Herb Interactions

Ethanol: Caution with ethanol (may increase hypoglycemia).

Food: Insulin shifts potassium from extracellular to intracellular space. Decreases potassium serum concentration.

Herb/Nutraceutical: Use caution with chromium, garlic, gymnema (may increase hypoglycemia).


Stability

Newer neutral formulation of regular insulin is stable at room temperature up to one month (studies indicate up to 24-30 months)

Insulin aspart (NovoLog®) and insulin glulisine (Apidra™): Can be infused SubQ by external insulin pump; do not dilute or mix with other insulins when used in an external pump for SubQ infusion; insulin in reservoir should be replaced every 48 hours. Do not expose to temperatures 37°C (98.6°F).

Insulin glargine (Lantus®): When refrigeration is unavailable, 10 mL vials may be stored at room temperature for up to 28 days; solution not used within this time must be discarded.

Insulin lispro (Humalog®): Prior to use, store in refrigerator; do not use if it has been frozen. If not refrigerated, use within 28 days and protect from heat and light. Once opened (in-use), vials may be stored in refrigerator or for up to 28 days at room temperature. Cartridges/pens should be stored at room temperature and used within 28 days.

Freezing causes more damage to insulin than room temperatures up to 100°F. Avoid direct sunlight.

Compatibility of insulin preparations:

Rapid-acting:

Insulin injection (regular): Compatible mixed with all types insulin

Lispro (Humalog®): Compatible mixed with Ultralente® / NPH

Insulin aspart (NovoLog®): Compatible mixed with NPH human insulin

Intermediate-acting: Isophane insulin suspension (NPH): Compatible mixed with regular insulin

Long-acting: When mixing with NPH insulin in any proportion, the excess protamine may combine with regular insulin and may reduce or delay activity of regular insulin (does not appear to be clinically significant); phosphate-buffered regular insulins bind with Lente® insulins forming short-acting insulin; excess protamine in PZI combines with regular insulin and prolongs its action, therefore, should not be mixed; administer as a separate injection; insulin glargine (Lantus®) cannot be diluted or mixed with any other insulin or solution

Stability of parenteral admixture of regular insulin at room temperature (25°C) and at refrigeration temperature (4°C): 24 hours

Standard diluent for regular insulin: 100 units/100 mL NS

Comments: All bags should be prepared fresh; tubing should be flushed 30 minutes prior to administration to allow adsorption as time permits


Compatibility

 Buffered insulin (Velosulin® BR) should not be mixed with any other form of insulin. Isophane insulin suspension (NPH) is compatible with regular insulin. Protamine zinc insulin suspension is compatible with regular insulin. Insulin glulisine (Apidra™) may be mixed with NPH insulin in the same syringe (glulisine should be withdrawn first).

Insulin (regular) : Variable stability (consult detailed reference) in NS, TPN

Y-site administration: Compatible: Alatrofloxacin, amiodarone, ampicillin, ampicillin/sulbactam, aztreonam, cefazolin, cefotetan, clarithromycin, dobutamine, esmolol, famotidine, gentamicin, heparin, heparin with hydrocortisone sodium succinate, imipenem/cilastatin, indomethacin, magnesium sulfate, meperidine, meropenem, midazolam, milrinone, morphine, nitroglycerin, oxytocin, pentobarbital, potassium chloride, propofol, ritodrine, sodium bicarbonate, sodium nitroprusside, tacrolimus, terbutaline, ticarcillin, ticarcillin/clavulanate potassium, tobramycin, vancomycin, vitamin B complex with C. Incompatible: Dopamine, nafcillin, norepinephrine, ranitidine. Variable (consult detailed reference): Digoxin, diltiazem, labetalol, levofloxacin, TPN

Compatibility in syringe: Compatible: Metoclopramide

Compatibility when admixed: Compatible: Bretylium, cimetidine, lidocaine, meropenem, verapamil. Incompatible: Aminophylline, amobarbital, chlorothiazide, cytarabine, dobutamine, methylprednisolone sodium succinate, octreotide, pentobarbital, phenobarbital, phenytoin, thiopental. Variable (consult detailed reference): Ranitidine


Mechanism of Action

 The principal hormone required for proper glucose utilization in normal metabolic processes; it is obtained from beef or pork pancreas or a biosynthetic process converting pork insulin to human insulin; insulins are categorized into 3 groups related to promptness, duration, and intensity of action


Pharmacodynamics/Kinetics

Onset of action and duration: Biosynthetic NPH human insulin shows a more rapid onset and shorter duration of action than corresponding porcine insulins; human insulin and purified porcine regular insulin are similarly efficacious following SubQ administration. The duration of action of highly purified porcine insulins is shorter than that of conventional insulin equivalents. Duration depends on type of preparation and route of administration as well as patient-related variables. In general, the larger the dose of insulin, the longer the duration of activity.

Absorption: Biosynthetic regular human insulin is absorbed from the SubQ injection site more rapidly than insulins of animal origin (60-90 minutes peak vs 120-150 minutes peak respectively) and lowers the initial blood glucose much faster. Human Ultralente® insulin is absorbed about twice as quickly as its bovine equivalent, and bioavailability is also improved. Human Lente® insulin preparations are also absorbed more quickly than their animal equivalents. Insulin glargine (Lantus®) is designed to form microprecipitates when injected subcutaneously. Small amounts of insulin glargine are then released over a 24-hour period, with no pronounced peak. Insulin glargine (Lantus®) for the treatment of type 1 diabetes (insulin dependent, IDDM) and type 2 diabetes mellitus (noninsulin dependent, NIDDM) in patients who require basal (long-acting) insulin.

Bioavailability: Medium-acting SubQ Lente®-type human insulins did not differ from the corresponding porcine insulins

Insulin aspart (NovoLog®):

Onset: 0.17-0.33 hours; Peak effect: 1-3 hours; Duration: 3-5 hours

Insulin lispro (Humalog®), insulin glulisine (Apidra™):

Onset: 0.25 hours; Peak effect: 0.5-1.5 hours; Duration: 6-8 hours

Insulin, regular (Novolin® R):

Onset: 0.5-1 hours; Peak effect: 2-3 hours; Duration: 8-12 hours

Isophane insulin suspension (NPH) (Novolin® N):

Onset: 1-1.5 hours; Peak effect: 4-12 hours; Duration: 24 hours

Insulin zinc suspension (Lente®):

Onset: 1-2.5 hours; Peak effect: 8-12 hours; Duration: 18-24 hours

Isophane insulin suspension and regular insulin injection (Novolin® 70/30):

Onset: 0.5 hours; Peak effect: 2-12 hours; Duration: 24 hours

Extended insulin zinc suspension (Ultralente®):

Onset: 4-8 hours; Peak effect: 16-18 hours; Duration: >36 hours

Insulin glargine (Lantus®):

Duration: 24 hours


Dosage

 Dose requires continuous medical supervision; may administer I.M., or SubQ; regular insulin may also be administered I.V.

Diabetes mellitus: The number and size of daily doses, time of administration, and diet and exercise require continuous medical supervision. In addition, specific formulations may require distinct administration procedures (see Administration).

Children and Adults: 0.5-1 unit/kg/day in divided doses

Adolescents (growth spurts): 0.8-1.2 units/kg/day in divided doses

Adjust dose to maintain premeal and bedtime blood glucose of 80-140 mg/dL (children <5 years: 100-200 mg/dL)

Insulin glargine (Lantus®): SubQ:

Type 2 diabetes (patient not already on insulin): 10 units once daily, adjusted according to patient response (range in clinical study 2-100 units/day)

Patients already receiving insulin: In clinical studies, when changing to insulin glargine from once-daily NPH or Ultralente® insulin, the initial dose was not changed; when changing from twice-daily NPH to once-daily insulin glargine, the total daily dose was reduced by 20% and adjusted according to patient response

Hyperkalemia (unlabeled use): Administer dextrose at 0.5-1 mL/kg and regular insulin 1 unit for every 4-5 g dextrose given

Diabetic ketoacidosis: Children and Adults: Regular insulin: I.V. loading dose: 0.1 unit/kg, then maintenance continuous infusion: 0.1 unit/kg/hour (range: 0.05-0.2 units/kg/hour depending upon the rate of decrease of serum glucose - too rapid decrease of serum glucose may lead to cerebral edema).

Optimum rate of decrease (serum glucose): 80-100 mg/dL/hour

Note: Newly-diagnosed patients with IDDM presenting in DKA and patients with blood sugars <800 mg/dL may be relatively "sensitive" to insulin and should receive loading and initial maintenance doses approximately 1 /2 of those indicated above.

Dosing adjustment in renal impairment (regular): Insulin requirements are reduced due to changes in insulin clearance or metabolism

Clcr 10-50 mL/minute: Administer at 75% of normal dose

Clcr<10 mL/minute: Administer at 25% to 50% of normal dose and monitor glucose closely

Hemodialysis: Because of a large molecular weight (6000 daltons), insulin is not significantly removed by either peritoneal or hemodialysis

Supplemental dose is not necessary

Peritoneal dialysis: Supplemental dose is not necessary

Continuous arteriovenous or venovenous hemofiltration effects: Supplemental dose is not necessary


Administration

SubQ administration: Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, buttocks, or abdomen, with sites rotated. When mixing regular insulin with other preparations of insulin, regular insulin should be drawn into syringe first. Buffered insulin (Velosulin® BR) should not be mixed with any other form of insulin.

Insulin lispro (Humalog®): May be administered within 15 minutes before or immediately after a meal.

Insulin glulisine (Apidra™): Should be administered within 15 minutes before or within 20 minutes after start of meal. Can be infused SubQ by external insulin pump; do not dilute or mix with other insulins when used in an external pump for SubQ infusion; should replace insulin in reservoir every 48 hours.

Insulin aspart (NovoLog®): Should be administered immediately before a meal (within 5-10 minutes of the start of a meal). Can be infused SubQ by external insulin pump; do not dilute or mix with other insulins when used in an external pump for SubQ infusion; should replace insulin in reservoir every 48 hours.

Human regular insulin: Should be administered within 30-60 minutes before a meal.

Intermediate-acting insulins (such as NPH): May be administered 1-2 times/day.

Long-acting insulins (such as Ultralente®, Lantus®): May be administered once daily.

Insulin glargine (Lantus®): Should be administered once daily, at any time of day, but should be administered at the same time each day. Cannot be diluted or mixed with any other insulin or solution.

Regular insulin may be administered by SubQ, I.M., or I.V. routes

I.V. administration (requires use of an infusion pump): Only regular insulin may be administered I.V.

I.V. infusions: To minimize adsorption problems to I.V. solution bag:

If new tubing is not needed: Wait a minimum of 30 minutes between the preparation of the solution and the initiation of the infusion

If new tubing is needed: After receiving the insulin drip solution, the administration set should be attached to the I.V. container and the line should be flushed with the insulin solution. The nurse should then wait 30 minutes, then flush the line again with the insulin solution prior to initiating the infusion

If insulin is required prior to the availability of the insulin drip, regular insulin should be administered by I.V. push injection

Because of adsorption, the actual amount of insulin being administered could be substantially less than the apparent amount. Therefore, adjustment of the insulin drip rate should be based on effect and not solely on the apparent insulin dose. Furthermore, the apparent dose should not be used as the basis for determining the subsequent insulin dose upon discontinuing the insulin drip. Dose requires continuous medical supervision.

To be ordered as units/hour

Example: Standard diluent of regular insulin only: 100 units/100 mL NS (can be administered as a more diluted solution, ie, 100 units/250 mL NS)

Insulin rate of infusion (100 units regular/100 mL NS)

1 unit/hour: 1 mL/hour

2 units/hour: 2 mL/hour

3 units/hour: 3 mL/hour

4 units/hour: 4 mL/hour

5 units/hour: 5 mL/hour, etc


Monitoring Parameters

 Urine sugar and acetone, serum glucose, electrolytes, Hb A1c, lipid profile


Reference Range

Therapeutic, serum insulin (fasting): 5-20 IU/mL (SI: 35-145 pmol/L)

Glucose, fasting:

Newborns: 60-110 mg/dL

Adults: 60-110 mg/dL

Elderly: 100-180 mg/dL


Dietary Considerations

 Dietary modification based on ADA recommendations is a part of therapy. Monitor potassium serum concentration.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication is used to control diabetes; it is not a cure. It is imperative to follow other components of prescribed treatment (eg, diet and exercise regimen). Take exactly as directed. Do not change dose or discontinue unless advised by prescriber. With insulin aspart (NovoLog®), you must start eating within 5-10 minutes after injection. Insulin glulisine (Apidra™) should be administered within 15 minutes before or within 20 minutes after start of meal. If you experience hypoglycemic reaction, contact prescriber immediately. Always carry quick source of sugar with you. Monitor glucose levels as directed by prescriber. Report adverse side effects, including chest pain or palpitations; persistent fatigue, confusion, headache; skin rash or redness; numbness of mouth, lips, or tongue; muscle weakness or tremors; vision changes; respiratory difficulty; or nausea, vomiting, or flu-like symptoms. Pregnancy precaution: Inform prescriber if you are or intend to become pregnant.


Additional Information

 The term "purified" refers to insulin preparations containing no more than 10 ppm proinsulin (purified and human insulins are less immunogenic). Buffering agent in Velosulin® BR may alter the activity of other insulin products.


Anesthesia and Critical Care Concerns/Other Considerations

 Intensive insulin therapy in critically-ill patients may have beneficial effects on mortality and morbidity. Van den Berghe and colleagues performed a single center, prospective, randomized, controlled study in 1548 surgical intensive care patients. Authors compared "conventional" control of blood glucose (180-200 mg/dL) versus "intensive" control of blood glucose (80-110 mg/dL). Primary outcome was ICU mortality. The authors showed an absolute mortality reduction of 3.4% (8.0 vs 4.6%; p: <0.04). Intensive insulin therapy also reduced bloodstream infections (7.8 vs 4.2%; p: 0.003), acute renal failure requiring hemodialysis (8.2 vs 4.8%; p: 0.007), and critical-illness polyneuropathy (51.9 vs 28.7%; p: <0.001). Greatest mortality reduction appeared in patients with an ICU stay >5 days, reducing mortality by 9.6% (20.2 vs 10.6%; p: 0.005). Other authors have shown intensive insulin therapy to reduce morbidity and mortality after myocardial infarction and coronary bypass.


Cardiovascular Considerations

 Hyperglycemia (blood glucose >110 mg/dL) increases in-hospital mortality and CHF in patients admitted with acute myocardial infarction. The 2004 ACC/AHA STEMI guidelines recommend an insulin infusion to normalize blood glucose in patients with STEMI and complicated courses. The American College of Endocrinology recommends patients in an intensive care setting maintain serum glucose levels 110 mg/dL. In other inpatient units, patients may have preprandial glucoses 110 mg/dL and maximal glucose 180 mg/dL.


Dental Health: Effects on Dental Treatment

 Type 1 diabetics (insulin-dependent) should be appointed for dental treatment in the morning in order to minimize chance of stress-induced hypoglycemia.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause drowsiness or confusion


Mental Health: Effects on Psychiatric Treatment

 MAO inhibitors may enhance the hypoglycemic effects of insulin; TCAs may antagonize the effects of insulin


Dosage Forms

 [DSC] = Discontinued product

RAPID-ACTING:

Injection, solution, aspart, human:

NovoLog®: 100 units/mL (10 mL vial)

NovoLog® [InnoLet®]: 100 units/mL (3 mL prefilled syringe)

NovoLog® [PenFill®]: 100 units/mL (3 mL cartridge)

Injection, solution, lispro, human (Humalog®): 100 units/mL (1.5 mL cartridge [DSC], 3 mL disposable pen, 10 mL vial)

Injection, solution, glulisine (Apidra™): 100 units/mL (10 mL vial)

SHORT-ACTING:

Injection, solution, regular, human:

Humulin® R: 100 units/mL (10 mL vial)

Novolin® R: 100 units/mL (1.5 mL prefilled syringe, 10 mL vial)

Novolin® R [PenFill®]: 100 units/mL (1.5 mL cartridge, 3 mL cartridge)

Injection, solution, regular, human, buffered (Velosulin® BR) [DSC]: 100 units/mL (10 mL vial)

Injection, solution, regular, human, concentrate (Humulin® R U-500): 500 units/mL (20 mL vial)

Injection, solution, regular, purified pork (Regular Iletin® II): 100 units/mL (10 mL vial)

INTERMEDIATE-ACTING:

Injection, suspension, lente, human [zinc] (Humulin® L, Novolin® L [DSC]): 100 units/mL (10 mL vial)

Injection, suspension, lente, purified pork [zinc] (Lente® Iletin® II): 100 units/mL (10 mL vial) [DSC]

Injection, suspension, NPH, human [isophane]:

Humulin® N: 100 units/mL (3 mL disposable pen, 10 mL vial)

Novolin® N: 100 units/mL (1.5 mL prefilled syringe, 10 mL vial)

Novolin® N [PenFill®]: 100 units/mL (1.5 mL cartridge, 3 mL cartridge)

Injection, suspension, NPH, purified pork [isophane] (NPH Iletin® II): 100 units/mL (10 mL vial)

LONG-ACTING:

Injection, suspension, Ultralente®, human [zinc] (Humulin U Ultralente®): 100 units/mL (10 mL vial)

Injection, solution, glargine, human (Lantus®): 100 unit/mL (10 mL vial)

COMBINATION, INTERMEDIATE-ACTING:

Injection, aspart protamine human suspension 70% and rapid-acting aspart human solution 30% (NovoLog® Mix 70/30): 100 units/mL (3 mL cartridge, 3 mL prefilled syringe)

Injection, lispro protamine human suspension 75% and rapid-acting lispro human solution 25% (Humalog® Mix 75/25™): 100 units/mL (3 mL disposable pen, 10 mL vial)

Injection, NPH human insulin suspension 50% and short-acting regular human insulin solution 50% (Humulin® 50/50): 100 units/mL (10 mL vial)

Injection, NPH human insulin suspension 70% and short-acting regular human insulin solution 30%:

Humulin® 70/30: 100 units/mL (3 mL disposable pen, 10 mL vial)

Novolin® 70/30: 100 units/mL (1.5 mL prefilled syringe, 10 mL vial)

Novolin® 70/30 [PenFill®]: 100 units/mL (1.5 mL cartridge, 3 mL cartridge)


References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Brown G and Dodek P, "Intravenous Insulin Nomogram Improves Blood Glucose Control in the Critically Ill," Crit Care Med , 2001, 29(9):1714-9.

Campbell IW and Ratcliffe JG, "Suicidal Insulin Overdosage Managed Exclusively by Excision of Insulin Injection Site," Br Med J (Clin Res Ed) , 1982, 285(6339):408-9.

Fath-Ordoubadi F and Beatt KJ, "Glucose-Insulin-Potassium Therapy for Treatment of Acute Myocardial Infarction: An Overview of Randomized Placebo-Controlled Trials," Circulation , 1997, 96(4):1152-6.

Hopkins DF, Cotton SJ, and Williams G, "Effective Treatment of Insulin-Induced Edema Using Ephedrine," Diabetes Care , 1993, 16(7):1026-8.

Joint Commission on Accreditation of Healthcare Organizations, "2005 National Patient Safety Goals," available at http://www.jcaho.org/accredited+organizations/patient+safety/05_npsg_guidelines Last accessed October 15, 2004.

Lazar HL, Philippides G, Fitzgerald C, et al, "Glucose-Insulin-Potassium Solutions Enhance Recovery After Urgent Coronary Artery Bypass Grafting," J Thorac Cardiovasc Surg , 1997, 113(2):354-60.

Levine DF and Bulstrode C, "Managing Suicidal Insulin Overdose," Br Med J (Clin Res Ed) , 1982, 285(6346):974-5.

Malmberg K, "Prospective Randomised Study of Intensive Insulin Treatment on Long Term Survival After Acute Myocardial Infarction in Patients With Diabetes Mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group," BMJ , 1997, 314(7093):1512-5.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Morley JE and Perry HM 3d, "The Management of Diabetes Mellitus in Older Individuals," Drugs , 1991, 41(4):548-65.

Mueller-Schoop J, "Accidental Intravenous Self-Injection With Insulin Pen," Lancet , 1993, 341(8849):894.

Nathan DM, "Insulin Treatment in the Elderly Diabetic Patient," Clin Geriatr Med , 1990, 6(4):923-31.

Pickup J, "Human Insulin: Problems With Hypoglycaemia in a Few Patients," BMJ , 1989, 299(6706):991-3.

"Proceedings of the American College of Endocrinology Task Force on Inpatient Diabetes and Metabolic Control Consensus Conference, Washington, DC, USA, December 2003," Endocr Pract , 2004, (10 Suppl 2):3-108.

Roberge RJ, Martin TG, and Delbridge TR, "Intentional Massive Insulin Overdose: Recognition and Management," Ann Emerg Med , 1993, 22(2):228-34.

Simeon PS, Geffner ME, Levin SR, et al, "Continuous Insulin Infusions in Neonates: Pharmacologic Availability of Insulin in Intravenous Solutions," J Pediatr , 1994, 124(5 Pt 1):818-20.

Van den Berghe G, Wouters P, Weekers F, et al, "Intensive Insulin Therapy in the Critically Ill Patients," N Engl J Med , 2001, 345(19):1359-67.


International Brand Names

 Berlinsulin H 20/80® [biosyn./ 20% sol./80% isoph.] (DE); Berlinsulin H 30/70® [biosyn./ 30% sol./70% isoph.] (DE); Berlinsulin H Basal® [biosyn.] (DE); B-Insulin S Berlin-Chemie® [porcine] (DE); Bio-Insulin 30/70® [biosyn./ 30% sol./70% isoph.] (IT); Bio-Insulin 50/50® [biosyn./ 50% sol./50% isoph.] (IT); Bio-Insulin I® [biosyn.] (IT); Bio-Insulin L® [biosyn.] (IT); Bio-Insulin U® [biosyn.] (IT); Gensulin M10® [biosyn./ 10% sol./90% isoph.] (PL); Gensulin M20® [biosyn./ 20% sol./80% isoph.] (PL); Gensulin M30® [biosyn./ 30% sol./70% isoph.] (PL); Gensulin M40® [biosyn./ 40% sol./60% isoph.] (PL); Gensulin M50® [biosyn./ 50% sol./50% isoph.] (PL); Gensulin N® [biosyn.] (PL); Humalog® (CA); Humalog® Mix 25™ (CA); Huminsulin Basal® (CH, DE); Huminsulin Lilly® (AT); Huminsulin Profil I® [10% sol./90% isoph.] (CH, DE); Huminsulin Profil II® [20% sol./80% isoph.] (CH, DE); Huminsulin Profil III® [30% sol./70% isoph.] (CH, DE); Huminsulin Profil IV® [40% sol./60% isoph.] (CH, DE); Humulin 10/90® [10% sol./90% isoph.] (RO, SI); Humulin 20/80® [20% sol./80% isoph.] (AU, IL, MX, NZ, PL, RO, SI); Humulin 30/70® [30% sol./70% isoph.] (AU, CR, DO, GT, HN, ID, IT, MX, NO, NZ, PA, PL, RO, SE, SG, SI, SV); Humulin 40/60® [40% sol./60% isoph.] (RO, SI); Humulin 50/50® [50% sol./50% isoph.] (AU, IT, RO); Humulin 70/30® [30% sol./70% isoph.] (AR, CO, ID, IL, TH, TR); Humulina 10/90® [10%sol./90% isoph.] (ES); Humulina 20/80® [20%sol./80% isoph.] (ES); Humulina 30/70® [30%sol./70% isoph.] (ES); Humulina 40/60® [40%sol./60% isoph.] (ES); Humulina 50/50® [50%sol./50% isoph.] (ES); Humulina Lenta® (ES); Humulina NPH® (ES); Humulina Ultralenta® (ES); Humulin® (CA, GB, IE, SE); Humuline 10/90® [10% sol./90% isoph.] (NL); Humuline 20/80® [20% sol./80% isoph.] (BE, NL); Humuline 30/70® [30% sol./70% isoph.] (BE, NL); Humuline 40/60® [40% sol./60% isoph.] (BE, NL); Humuline 50/50® [50% sol./50% isoph.] (BE, NL); Humuline Long® (BE); Humuline NPH® (BE, NL); Humuline Ultralong® (BE); Humulin I® (GB, IE, IT); Humulin L® (AR, AU, CR, DO, GB, GT, HN, HU, IT, MX, NZ, PA, PL, PT, RO, RU, SG, SV); Humulin Lenta® (ES); Humulin Lente® (GB); Humulin M1® [10% sol./90% isoph.] (RO); Humulin M2® [20% sol./80% isoph.] (GB, HR, HU, PL, PT, RU, YU); Humulin M3® [30% sol./70% isoph.] (CZ, GB, HR, HU, IE, PL, PT, RU, YU); Humulin M4® [40% sol./60% isoph.] (HU); Humulin M5® [50% sol./50% isoph.] (GB); Humulin M® [20% sol./80% isoph.] (HR, TR); Humulin N® (AR, BD, CO, CR, CZ, DO, GT, HN, HR, HU, ID, IL, MX, NZ, PA, PL, SG, SI, SV, TH, TR); Humulin NPH® (AU, DK, FI, PT, RO, RU, SE, SI, TR, YU); Humulin S® (GB); Humulin U® (HU, IL, IT, NZ, PL, PT); Humulin UL® (AU); Humulin Zn® (GB, IE); Iletin® II Pork (CA); Insuhuman Basal® (NL); Insuhuman Comb 15® [semisyn./ 15% sol./85% isoph.] (NL); Insuhuman Comb 25® [semisyn./ 25% sol./75% isoph.] (NL); Insuhuman Comb 50® [semisyn./ 50% sol./50% isoph.] (NL); Insulina Betalin® (AR); Insulin Actraphane 10/90 HM® [10% sol./90% isoph.] (DE, IT, JP); Insulin Actraphane 20/80 HM® [20% sol./80% isoph.] (DE, IT, JP); Insulin Actraphane 30/70 HM® [30% sol./70% isoph.] (DE, IT, JP); Insulin Actraphane 40/60 HM® [40% sol./60% isoph.] (DE, IT, JP); Insulin Actraphane 50/50 HM® [50% sol./50% isoph.] (DE, IT, JP); Insulin Actraphane HM® (HR); Insulin B.Braun ratiopharm Basal® (DE); Insulin B.Braun ratiopharm Comb 30/70® [30% sol./70% isoph.] (DE); Insulin-HM® (CZ); Insulin-HM Mix® [30% sol./70% isoph.] (CZ); Insulin Homofan® (HR, SI); Insulin Homolong 40® (HR, RU); Insulin Humacart® (JP); Insulin Humaject 20/80® [20% sol./80% isoph.] (BE, PL, YU); Insulin Humaject 30/70® [30% sol./70% isoph.] (BE, GB, HR, PL, SI, YU); Insulin Humaject 40/60® [40% sol./60% isoph.] (BE); Insulin Humaject 50/50® [50% sol./50% isoph.] (BE); Insulin HumaJect M3® (GB, HR); Insulin Humaject N® (HR, PL); Insulin Humaject NPH® (BE, HR, SI, YU); Insulin Humaject R® (HR); Insulin Humalog Mix 25® [25% sol./75% isoph.] (AT, AU, CH, DE, DK, ES, FI, FR, GB, HR, IE, IL, IT, NL, NO, PL, RO, SE, SG, SI, TH); Insulin Humalog Mix 50® [50% sol./50% isoph.] (AT, CH, DE, DK, ES, FR, GB, HR, IE, PL, RO, SE, SI); Insulin Humaplus 20/80® [20%sol./80% isoph.] (ES); Insulin Humaplus 30/70® [30% sol./70% isoph.] (ES); Insulin Humaplus 40/60® [40% sol./60% isoph.] (ES); Insulin Humaplus 50/50® [50% sol./50% isoph.] (ES); Insulin Humaplus NPH® (ES); Insulin Hypurin Bovine Isophane® [bovine] (CZ, GB); Insulin Hypurin Bovine Lente® [bovine] (GB); Insulin Hypurin Bovine Protamine Zinc® [bovine] (GB); Insulin Hypurin Bovine Protamin Zink Sulfat® [bovine] (CZ); Insulin Hypurin Porcine 30/70 Mix® [porcine, 30% sol./70% isoph.] (CH, GB); Insulin Hypurin Porcine Isophane® [porcine] (CH, GB); Insulin Iletin II Lente® [porcine] (RO, RU); Insulin Iletin II NPH® [porcine] (RO, RU); Insulin Insulatard® (DK, GB, IE, IL, PL, SE); Insulin Insulatard HM® (AT, BE, CH, CZ, DK, DO, ES, FR, GB, HR, HU, ID, IE, IL, NL, NO, PL, PT, RO, SE, SG, SI, TH, TR, YU); Insulin Insulatard Human (DE); Insulin Insulatard MC® [porcine] (CH); Insulin Isofan HM® (YU); Insulin Isuhuman Basal® (PT); Insulin Isuhuman Comb 25® [semisyn./ 25% sol./75% isoph.] (PT); Insulin Lantus® (AR, AT, BE, CH, DE, ES, FR, GB, HR, IE, IL, IT, JP, NO, NZ, PL, RO, SE, SI, YU); Insulin Lantus OptiSet® (SE); Insulin Lente HM® [30% amorph./70% cryst.] (YU); Insulin Lente MC® [30% porcine amorph./70% bovine cryst.] (RO); Insulin Lente SPP® [porcine/ 30% amorph./70% cryst.] (YU); Insulin Mixtard 10/90® (SE); Insulin Mixtard 10 HM® [10% sol./90% isoph.] (BE, CH, CZ, ES, FR, GB, HR, HU, IE, IL, JP, NL, NO, PL, PT, RU, SI, TR, YU); Insulin Mixtard 20/80® (SE); Insulin Mixtard 20 HM® [20% sol./80% isoph.] (BE, CH, CZ, ES, FR, GB, HR, HU, IE, IL, JP, NL, NO, PL, PT, RO, RU, SG, SI, TR, YU); Insulin Mixtard 30/70 Human (DE, RU); Insulin Mixtard 30/70® (SE); Insulin Mixtard 30 HM® [30% sol./70% isoph.] (BE, CH, CZ, ES, FR, GB, HR, HU, ID, IE, IL, JP, NL, NO, NZ, PL, PT, RO, RU, SG, SI, TH, TR, YU); Insulin Mixtard 30 MC® [porcine, 30% sol./70% isoph.] (CH); Insulin Mixtard 40/60® (SE); Insulin Mixtard 40 HM® [40% sol./60% isoph.] (BE, CH, CZ, ES, FR, GB, HR, HU, IE, IL, JP, NL, NO, PL, PT, RO, RU, SI, TR, YU); Insulin Mixtard 50/50® (SE); Insulin Mixtard 50 HM® [50% sol./50% isoph.] (BE, CH, CZ, ES, FR, GB, HR, HU, IE, IL, JP, NL, NO, NZ, PL, PT, RO, RU, SG, SI, TR, YU); Insulin Mixtard HM 10%/90%® [10% sol./90% isoph.] (AT, FI); Insulin Mixtard HM 20%/80%® [20% sol./80% isoph.] (AT, AU, FI); Insulin Mixtard HM 30%/70%® [30% sol./70% isoph.] (AT, AU, DK, ES, FI); Insulin Mixtard HM 40%/60%® [40% sol./60% isoph.] (AT, FI); Insulin Mixtard HM 50%/50%® [50% sol./50% isoph.] (AT, AU, FI); Insulin Mixtard HM® (GB, PL, TH, TR); Insulin Mixtard® (SE); Insulin-Mono D® [bovine/porcine] (CZ); Insulin Monotard HM® (AT, AU, BE, CH, CZ, DE, DK, DO, ES, FI, FR, GB, HR, HU, ID, IE, IL, IT, JP, NL, NO, NZ, PL, PT, RO, RU, TH, YU); Insulin Monotard MC® [porcine] (HU, PL, RO, RU, YU); Insulin Monotard® (NZ, SE); Insulin Novolin 30/70® [30% sol./70% isoph.] (MX); Insulin Novolin 30R® [30% sol./70% isoph.] (JP); Insulin Novolin 70/30® [70% sol./30% isoph.] (CO); Insulin Novolin L® (MX); Insulin Novolin N® (CO, JP, MX); Insulin Novolin U® (JP); Insulin NovoMix® [30% sol./70% isoph.] (AT, BE, DE, DK, ES, FI, FR, GB, HR, PL, RO, SE, SI, YU); Insulin Novo Nordisk® (AT); Insulin Novorapid® (AT, AU, BE, CH, CZ, DE, DK, ES, FI, FR, GB, HR, HU, IE, IT, NL, NO, NZ, PL, RO, SE, SG, SI, TR, YU); Insulin Novo Semilente® [porcine] (DE); Insulin Penmix 10® [10% sol./90% isoph.] (NZ); Insulin Penmix 20® [20% sol./80% isoph.] (NZ); Insulin Penmix 30® [30% sol./70% isoph.] (NZ); Insulin Penmix 40® [40% sol./60% isoph.] (NZ); Insulin Penmix 50® [50% sol./50% isoph.] (NZ); Insulin Pork Insulatard® [porcine] (GB); Insulin Pork Mixtard® [porcine, 30% sol./70% isoph.] (GB); Insulin Protaphan® (DE, FI); Insulin Protaphane HM® (DE, IT, RU); Insulin Protaphane® (HR, NZ); Insulin Protaphane MC® (RU); Insulin Semilente MC® [porcine] (CH, HU); Insulin S.N.C. Berlin-Chemie® [porcine] (DE); Insulin Ultratard HM® (AT, AU, BE, CH, CZ, DE, ES, FI, FR, GB, HR, HU, IE, IL, IT, NL, NO, NZ, PL, PT, RO, RU, SE, SG, YU); Insulinum Iso-Mix® [porcine] (PL); Insulinum Semilente® (PL); Insulin Umuline NPH® (FR); Insulin Umuline Profil 20® [20% sol./80% isoph.] (FR); Insulin Umuline Profil 30® [30% sol./70% isoph.] (FR); Insulin Umuline Zinc Composé® [30% amorph./70% cryst.] (FR); Insulin Umuline Zinc® (FR); Insulong GPP® [bovine] (HR); Insulong SPP® [porcine] (HR, RU); Insuman Basal® (AT, CH, CZ, DE, DK, FI, FR, GB, NL, NO, PL, RO, RU, SE, YU); Insuman Comb 15® [semisyn./ 15% sol./85% isoph.] (AT, CH, CZ, DE, FR, GB, IE, NL, PL, RU, YU); Insuman Comb 25® [semisyn./ 25% sol./75% isoph.] (AT, CH, CZ, DE, DK, FI, FR, GB, IE, NL, NO, PL, RO, RU, SE, YU); Insuman Comb 50® [semisyn./ 50% sol./50% isoph.] (AT, CH, CZ, DE, FR, GB, IE, NL, PL, RO, RU, YU); Insuman N® (AR, CO, CR, DO, EC, GT, HN, PA, SV); Insuman R® [semisyn.] (DO); Novolin® ge (CA); Novolin N HM® (EC); NovoRapid® (CA); Orgasulin® 70/30 [biosyn./ 30% sol./70% isoph.] (FR, TR); Orgasulin® NPH (TR)


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