Insulin Glargine (Systemic)
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VA CLASSIFICATION
Primary: HS501
Commonly used brand name(s): Lantus®.
Another commonly used name is:
Glargine HOE 71GT HOE 901 Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antidiabetic agent—
Indications
Accepted
Diabetes mellitus (treatment)—Insulin glargine is indicated in the treatment of diabetes mellitus for the control of hyperglycemia in adult and pediatric patients with type 1 diabetes and in adult patients with type 2 diabetes who require insulin{01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Analog of human insulin created by replacing the amino acid at position 21 of the A-chain (asparagine) with glycine and by adding two arginines to the C-terminus of the B-chain. {01} Synthesized by recombinant DNA process involving a genetically engineered Escherichia coli{01}.
Molecular weight—
6063{01}
pH
4{01}.
Mechanism of action/Effect:
Like other types of insulin, the primary action of insulin glargine is to regulate glucose metabolism{01}. Also, insulin glargine lowers the blood glucose concentration by stimulating glucose uptake especially by muscle and fat{01}. It also inhibits hepatic glucose production{01}.
Other actions/effects:
Insulin also inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.{01}
Absorption:
Insulin glargine was formulated to have a low aqueous solubility at neutral pH{01}. The insulin glargine solution has a pH of 4, and at this pH, it is completely soluble{01}. However, in the neutral pH of the subcutaneous tissue, microprecipitates are formed from which small amounts of insulin glargine are slowly released{01}. This results in a relatively constant concentration over 24 hours{01}. There is no pronounced peak with insulin glargine.{01}.
Like other insulins, the time course of action of insulin glargine may vary between individuals and within the same individual{01}. In contrast to other insulin products, the duration of action of insulin glargine was similar after subcutaneous injection into abdominal, deltoid, or thigh areas {01}.
Biotransformation:
In a human metabolism study, insulin glargine was partially metabolized at the carboxyl terminus of the B chain to two active metabolites, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30 B-Thr-insulin){01}. These metabolites have in vitro activity similar to that of insulin{01}.
Duration of action:
24 hours {01}
Precautions to Consider
Carcinogenicity
Two-year carcinogenicity studies were performed in mice and rats{01}. Doses up to 0.455 mg/kg were used which is for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 International Units (0.008 mg/kg/day) based on mg per square meter of body surface area (mg/m2){01}. For female mice, the findings were not conclusive because excessive mortality occurred in all dose groups{01}. Histiocytomas developed at injection sites in male rats (statistically significant) and male mice (not statistically significant) in groups receiving the acid vehicle{01}. Female animals, saline control, or insulin comparator groups using a different vehicle did not develop histiocytomas{01}. The relevance of these findings to humans is unknown {01}.
Mutagenicity
Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters). {01}
Pregnancy/Reproduction
Pregnancy—
Studies have not been done in humans. {01}
However, women with diabetes or a history of gestational diabetes must be educated about the necessity of maintaining good 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}
Administration of insulin glargine to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg per kilogram of body weight (approximately 7 times the recommended human subcutaneous starting dose of 10 International Units [0.008 mg/kg] based on mg/m 2) per day did not generally have effects that differed from regular human insulin. In Himalayan rabbits, doses of 0.072 mg per kilogram of body weight (approximately 2 times the recommended human subcutaneous starting dose of 10 International Units [0.008 mg/kg] based on mg/m 2) per day were administered during organogenesis. While the effects did not generally differ from regular human insulin, five rabbit fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Otherwise, early embryonic development appeared normal.{01}
FDA Pregnancy Category C. {01}
Breast-feeding
It is not known whether insulin glargine is distributed into breast milk. Women who are breast-feeding may require adjustments in their dosages of insulin glargine, in their meal plans, or in both.{01}
Pediatrics
Studies performed in patients 6 to 11 years of age with type 1 diabetes have not demonstrated pediatrics-specific problems that would limit the use of insulin glargine in children.{01}
Adolescents
Studies performed in patients 12 to 15 years of age with type 1 diabetes have not demonstrated adolescent-specific problems that would limit the use of insulin glargine in teenagers. {01}
Geriatrics
Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of insulin glargine in the elderly. Compared to the entire study population, patients 65 years and older had an expected higher incidence of cardiovascular events in the insulin glargine and NPH human insulin-treated groups. Because hypoglycemia may be more difficult to detect in the elderly, the initial dose, dose increments, and maintenance dose should be conservative to minimize the chance of hypoglycemic reactions.{01}
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.
Hyperglycemia-causing agents, such as:
Corticosteroids {01}
Danazol {01}
Diuretics {01}
Estrogens{01}
Isoniazid {01}
Oral contraceptives {01}
Phenothiazine derivatives {01}
Somatropin {01}
Sympathomimetic agents{01} or
Thyroid hormones {01} (these medications may cause loss of glycemic control; insulin requirements may be increased{01} )
Hypoglycemia-causing agents, such as:
Alcohol{01}
Antidiabetic agents{01}
Angiotensin-converting enzyme (ACE) inhibitors {01}
Disopyramide{01}
Fibrates{01}
Fluoxetine{01}
Monoamine oxidase (MAO) inhibitors {01}
Octreotide{01}
Propoxyphene{01}
Salicylates{01}or
Sulfonamides {01} (these medications may improve glucose control; insulin requirements may be decreased{01})
Pentamidine{01} (may cause hypoglycemia followed by hyperglycemia{01})
» Sympatholytics, such as:
Beta-adrenergic blocking agents{01}
Clonidine{01}
Guanethidine{01}or
Reserpine{01} (sympatholytics may mask some of the symptoms of hypoglycemia, making it more difficult to detect hypoglycemia{01})
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
» Diabetic ketoacidosis{01} (short-acting insulin administered intravenously is the preferred treatment for this condition{01})
Hypersensitivity to insulin glargine{01}
Intercurrent conditions, such as:
Emotional disturbances{01}
Infection{01}or
Stress{01} (may require adjustments in insulin or insulin glargine dosage)
Hepatic function impairment{01}or
Renal function impairment{01} (adjustment of insulin glargine dosage may be necessary{01})
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} (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} (anxiety; behavior change similar to drunkenness; blurred vision; cold sweats ; coma; confusion ; cool, pale skin; difficulty in concentrating; dizziness or lightheadedness; drowsiness; excessive hunger; fast heartbeat; headache ; nausea; nervousness; nightmares; restless sleep; seizures; shakiness; slurred speech; tingling in the hands, feet, lips, or tongue)
Note: Recovery from hypoglycemia may be delayed because insulin glargine has a long duration of effect.{01}
Incidence less frequent or rare
Allergy, systemic{01} (decrease in blood pressure; rapid pulse; shortness of breath; skin rash or itching over the entire body; sweating; wheezing)—may be life-threatening
{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Injection site pain{01}
Note: This reaction is usually mild and did not result in discontinuation of therapy.{01}
Incidence rare
Allergy, local{01} (itching, redness, or swelling at injection site )
Note: Within a few days to a few weeks, these minor symptoms usually resolve. Continuous rotation of the injection site will also minimize this reaction.{01}
edema{01} (bloating or swelling of face, hands, lower legs, and/or feet; rapid weight gain)
lipoatrophy{01} (depression of the skin at injection site)
lipohypertrophy{01} (thickening of the skin at injection site)
Overdose
For specific information on the agent used in the management of insulin glargine 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} See the package insert or Glucagon (Systemic) for specific dosing guidelines for the use of glucagon.
Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Insulin Glargine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to insulin glargine
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 glargine, in their meal plans, or in both
Other medications, especially sympatholytics
Other medical problems, especially diabetic ketoacidosis or hypoglycemia
Proper use of this medication
» Carefully reading patient instruction sheet contained in insulin glargine package 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
» Taking insulin glargine once daily at bedtime
» 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
Not taking other medications unless discussed with physician
Getting counseling for family members to help the patient with diabetes; also, special counseling for pregnancy planning and contraception
Discussing travel arrangements, including transporting insulin glargine, carrying medical history and extra supplies of insulin glargine and syringes or injection devices, and adjusting dosage if traveling across more than two time zones
» 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
» 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.
» Recognizing symptoms of hypoglycemia: anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; 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
» 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
» Recognizing what brings on symptoms of hyperglycemia, such as not taking enough or skipping a dose of insulin glargine or insulin; overeating or not following meal plan; having emotional stress or infection; or exercising less than usual
» 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
Side/adverse effects
Signs of potential side effects, especially hypoglycemia and systemic allergy
General Dosing Information
Insulin glargine should not be given intravenously because the prolonged duration of effect is dependent on injection into subcutaneous tissue. {01}
One international unit is equal to one unit; therefore, the dose is the same whether it is expressed in international units or units. {01}
The potency of insulin glargine is approximately the same as human insulin. {01}
The glucose-lowering profile of insulin glargine is relatively constant over 24 hours.{01}
Insulin glargine is administered once daily at bedtime. When patients are transferred from an intermediate- or long- acting insulin to insulin glargine, the dosage of the short-acting insulin or fast-acting insulin analog may require adjustment. The dosage of insulin glargine was usually NOT changed when patients were transferred from once-daily NPH human insulin or ultralente human insulin. For patients who were previously treated with twice-daily NPH human insulin, the initial dosage of insulin glargine was reduced by 20% and was subsequently based on patient response.{01}
Absorption patterns are similar after subcutaneous injection into the arm, abdomen, or leg indicating lack of injection-site dependency; however, injection sites within an injection area should be rotated with each injection. Like other insulin products, the rate of absorption may be affected by exercise and other variables.{01}
Changes in insulin strength, type (e.g., analog, NPH, regular), source (human or pork), method of manufacture (naturally occurring, recombinant DNA process), or manufacturer should be made cautiously and only under medical supervision. A change in any of these parameters may require an adjustment of insulin dosage.{01}
Parenteral Dosage Forms
INSULIN GLARGINE INJECTION
Usual Adult Dose and adolescent dose
Diabetes mellitus, type 1
Subcutaneous, dosage must be determined by the physician based on the patient's metabolic needs, eating habits, and other lifestyle variables. Insulin glargine is administered once daily at bedtime.{01}
Diabetes mellitus, type 2
Subcutaneous, for insulin-naive patients, the average initial dose is 10 International Units once daily at bedtime{01}
Usual Pediatric Dose
SeeUsual adult and adolescent dosefor children 6 years of age or older. Safety and efficacy have not been established in children less than 6 years old .{01}
Usual Geriatric Dose
SeeUsual adult dose.
Strength(s) usually available
U.S.—
100 International Units (3.6378 mg) of insulin glargine per mL (Rx) [Lantus® (zinc 30 mcg) (m-cresol 2.7 mg) (glycerol 85% 20 mg) (water for injection){01}]
Note: Insulin glargine is available in 5-mL and 10-mL vials and 3-mL cartridges. The cartridges should be used with the OptiPen™ One Insulin Delivery Device {01}
Packaging and storage:
Store unopened vials and cartridges in the refrigerator between 2 and 8 ° C (36 and 46 ° F). Do not store in the freezer. {01} However, after a cartridge has been placed in the OptiPen One delivery device, it should not be refrigerated.{01}
If refrigeration is not possible, the 10-mL vial and cartridge in use can be kept unrefrigerated for up to 28 days away from direct heat and light, as long as the temperature does not exceed 30° C(86° F). Unrefrigerated 10-mL vials and cartridges must be used within 28 days or they must be discarded. {01}
If refrigeration is not possible, the 5–mL vial in use can be kept unrefrigerated for up to 14 days away from direct heat and light, as long as the temperature does not exceed 30° C (86° F). Unrefrigerated 5–mL vials must be used within 14 days or they must be discarded. If the 5–mL vial is refrigerated, it may be used for up to 28 days.{01}
Stability:
Insulin glargine should not be diluted or mixed with any other insulin or solution.{01}
Auxiliary labeling:
• Do not freeze.
• Refrigerate.
Developed: 08/07/2000
References
- Product Information: Lantus®, insulin glargine. Aventis Pharmaceuticals Inc., Kansas City, MO, (PI revised 4/2000) reviewed 6/2000.
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