Insulin Analogs

Pronunciation: (IN-su-lin)
Class: Antidiabetic agent Insulin Aspart

Trade Names

NovoLog
- Injection 100 units/mL of human insulin aspart (rDNA)

NovoLog Mix 70/30
- Injection 100 units/mL of human insulin aspart (rDNA) (70% insulin aspart [rDNA] protamine suspension and 30% insulin aspart [rDNA])

NovoMix 30 (Canada)
NovoRapid (Canada)
Insulin Detemir

Levemir
- Injection 100 units/mL of insulin detemir (rDNA)

Insulin Glargine

Lantus
- Injection 100 units/mL of insulin glargine (rDNA)

Insulin Glulisine

Apidra
- Injection 100 units/mL of insulin glulisine (rDNA)

Insulin Lispro

Humalog
- Injection 100 units/mL of human insulin lispro (rDNA)

Humalog Mix 50/50
- Injection 100 units/mL of human insulin lispro (rDNA) (50% insulin lispro protamine suspension and 50% insulin lispro [rDNA])

Humalog Mix 75/25
- Injection 100 units/mL of human insulin lispro (rDNA) (75% insulin lispro protamine suspension and 25% insulin lispro [rDNA])

Pharmacology

Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and fat and inhibiting the output of glucose from the liver. Receptor-bound insulin also inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

Pharmacokinetics

Absorption

Insulin aspart mix

C _max is approximately 23 milliunits/L. T _max is approximately 1 h.

Insulin detemir

T _max is 6 to 8 h. Absolute bioavailability is 60%.

Insulin glulisine

C _max is approximately 83 microunits/mL. T _max is approximately 60 to 100 min. Absolute bioavailability is 70%.

Insulin lispro

T _max ranged from 30 to 90 min in patients with type 1 diabetes. Absolute bioavailability is 55% to 77%.

Insulin lispro mix 50/50

T _max ranged from 45 to 120 min in patients with type 1 diabetes.

Insulin lispro mix 75/25

T _max ranged from 30 to 240 min in patients with type 1 diabetes.

Distribution

Insulin aspart

0% to 9% bound to plasma proteins.

Insulin detemir

98% bound to albumin.

Insulin glulisine

Vd is 13 L.

Insulin lispro

Vd ranges from 0.26 to 0.36 L/kg.

Elimination

Insulin aspart

Cl is 1.22 L/h/kg. The half-life is 81 min.

Insulin aspart mix

The half-life is 8 to 9 h.

Insulin detemir

The half-life is 5 to 7 h (dose dependent). Vd is 0.1 L/kg.

Insulin glulisine

The half-life is 13 min after IV administration and 42 min after subcutaneous administration. Vd is 13 L.

Insulin lispro

The half-life is 1 h.

Peak

Insulin aspart

1 to 3 h.

Insulin aspart mix

1 to 4 h.

Insulin detemir

6 to 8 h.

Insulin glulisine

55 min.

Insulin lispro

0.5 to 1.5 h.

Duration

Insulin aspart

3 to 5 h.

Insulin aspart mix

Serum insulin levels return to baseline in approximately 12 h.

Insulin detemir

5.7 to 23.2 h (dose dependent).

Insulin glargine

24 h.

Insulin lispro

2 to 4 h.

Special Populations

Renal Function Impairment

Insulin Cl may be reduced in patients with impaired renal function.

Insulin aspart, insulin detemir

Renal function impairment does not appear to affect the pharmacokinetics.

Insulin aspart mix

Effects of renal function impairment on pharmacokinetics have not been studied.

Hepatic Function Impairment
Insulin aspart

No correlation between degree of hepatic failure and pharmacokinetics.

Insulin aspart mix, insulin glulisine

Effects of hepatic function impairment on pharmacokinetics have not been studied.

Elderly
Insulin aspart mix, insulin lispro, insulin lispro mix

Effects of age on pharmacokinetics have not been studied.

Insulin detemir

The AUC was 35% higher in healthy elderly patients (68 y and older) compared with younger patients (25 to 35 y of age) because of reduced Cl in elderly patients. Higher insulin detemir AUC levels in elderly patients because of reduced Cl.

Children
Insulin aspart, insulin glulisine

Pharmacokinetics in children and adolescents with type 1 diabetes are similar to those of healthy adults and adults with type 1 diabetes.

Insulin aspart mix, insulin lispro, insulin lispro mix

Pharmacokinetics have not been studied in children and adolescents.

Insulin detemir

AUC and C _max were higher by 10% and 24%, respectively, in children (6 to 12 y of age) compared with adolescents and adults.

Obesity Insulin aspart

Cl is reduced 28% in patients with a BMI more than 32 kg/m ² compared with patients with a BMI less than 23 kg/m ² .

Insulin aspart mix, insulin lispro, insulin lispro mix

Effects of obesity on pharmacokinetics have not been studied.

Insulin glulisine

T _max occurs faster and C _max is greater with insulin glulisine compared with regular human insulin.

Indications and Usage

Insulin aspart, insulin aspart mix, insulin lispro mix

Treatment of patients with diabetes mellitus for the control of hyperglycemia.

Insulin detemir, insulin glargine

Treatment of adults and children with type 1 diabetes or adults with type 2 diabetes mellitus who require long-acting insulin for control of hyperglycemia.

Insulin glulisine

Treatment of adults and children with diabetes mellitus for the control of hyperglycemia.

Insulin lispro

Treatment of adults and children 3 y and older with diabetes mellitus for the control of hyperglycemia.

Contraindications

During episodes of hypoglycemia (insulin aspart, insulin glulisine, insulin lispro, insulin lispro mix); hypersensitivity to any component.

Dosage and Administration

Insulin Aspart
Adults and Children Subcutaneous

Individualize dose (usual requirement, 0.5 to 1 units/kg/day), generally given immediately before a meal.

Insulin pump

When used in external insulin infusion pump, initial pump programming is based on total insulin dose of previous regimen. Although there is interpatient variability, approximately 50% of the total dose is given as meal-related boluses and remainder as basal infusion.

IV infusion

Possible under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia.

Insulin Aspart Mix
Adults

Subcutaneous Variable; generally administered twice daily (ie, before breakfast and dinner).

Insulin Detemir
Type 1 or Type 2 Diabetes on Basal or Basal-Bolus Treatment Adults and Children

Subcutaneous Change basal insulin to insulin detemir on a unit-to-unit basis, given once or twice daily, then adjust to achieve glycemic targets.

Type 2 Diabetes (Insulin-Naive) Adults and Children

Subcutaneous Start with 0.1 to 0.2 units/kg once daily in the evening or 10 units once or twice daily, then adjust dose to achieve glycemic targets.

Insulin Glargine
Insulin-Naive Adults and Children 6 y and older

Subcutaneous Start with 10 units daily and adjust according to patient needs; total daily dose ranges from 2 to 100 units.

Changeover From Intermediate- or Long-Acting Insulin Adults and Children 6 y and older

Subcutaneous In clinical studies, when transferring from once-daily neutral protamine Hagedorn (NPH) human insulin or ultralente human insulin to once-daily insulin glargine, the initial dose was usually not changed; however, when patients were transferred from twice-daily NPH human insulin to once-daily insulin glargine, the initial dose was usually reduced by 20%, and then adjusted based on patient response. When changing from a treatment regimen with an intermediate- or long-acting insulin, the amount and timing of short-acting insulin or fast-acting insulin analog, or the dose of any oral antidiabetic agent, may need to be adjusted.

Insulin Glulisine
Adults and Children 4 y and older

Subcutaneous, continuous subcutaneous infusion pump, IV Individualize dose. Insulin requirements vary, usually between 0.5 and 1 unit/kg/day.

Insulin Lispro
Adults and Children 3 y and older Subcutaneous

0.5 to 1 unit/kg/day. Individualize dose.

External subcutaneous pump

Individualize dose.

Insulin Lispro Mix
Adults

Subcutaneous Variable; generally administered twice daily.

General Advice

• Administer direct subcutaneous injections into abdominal wall, deltoid, or thigh. Rotate injection sites within same region.

• Insulin analog mixtures (eg, 75/25, 70/30, 50/50)
• For subcutaneous injection only. Not to be administered intradermal, IM, IV, intra-arterially, or by insulin infusion pump.
• Visually inspect and resuspend suspension immediately before use. Suspension must appear uniformly white and cloudy. Roll vial between palms 10 times. Roll prefilled cartridge or syringe between palms 10 times, then invert so that glass ball moves from one end of reservoir to the other. Repeat the inversion at least 10 times.
• Do not use if insulin substance remains separated from the liquid after mixing or if clumps or white particles are noted.
• Administer prescribed dose immediately (eg, 15 min for insulin lispro mix, or 10 to 20 min for insulin aspart mix) before a meal.
• Do not mix with any other insulin product.

• Insulin aspart
• For subcutaneous injection, subcutaneous infusion (insulin pump), or IV infusion only. Not for intradermal, IM, IV bolus, or intra-arterial administration.
• Used in combination with an intermediate- or long-acting insulin when used by direct subcutaneous injection.
• Do not administer if particulate matter, cloudiness, or discoloration is noted, or if solution has become viscous.
• Administer prescribed dose immediately (5 to 10 min) before a meal.
• If mixing insulin aspart with NPH human insulin, draw insulin aspart into syringe first and then administer prescribed dose immediately after mixing.
• Do not administer insulin mixtures IV.
• Do not mix insulin aspart with crystalline zinc insulin preparations (eg, Lente Iletin II , Humulin L , Humulin U ).
• Can be used alone when administered by subcutaneous infusion using external insulin pump.
• Place infusion catheter in abdominal wall. Rotate infusion sites within same region.
• Do not mix or dilute insulin aspart with any other insulin or solution when used in an external insulin pump for subcutaneous infusion.

• Insulin detemir
• For subcutaneous injection only. Not to be administered intradermally, IM, IV, intra-arterially, or by insulin infusion pump.
• Do not administer if particulate matter, cloudiness, or discoloration is noted, or if solution has become viscous.
• For once-daily dosing, administer with the evening meal or at bedtime.
• For twice-daily dosing, administer evening dose with evening meal, at bedtime, or 12 h after morning dose.
• Do not mix or dilute with any other insulin or solution.

• Insulin glargine
• For subcutaneous injection only. Not to be administered intradermally, IM, IV, intra-arterially, or by insulin infusion pump.
• Do not administer if particulate matter, cloudiness, or discoloration is noted, or if solution has become viscous.
• Administer once daily at any time during the day, but at the same time every day.
• If the insulin delivery device for insulin glargine cartridges malfunctions, the insulin glargine may be drawn from the cartridge system into a 100 unit syringe for injection.
• Do not mix or dilute with any other insulin or solution.

• Insulin glulisine
• Administer by subcutaneous injection into abdominal wall, thigh, or deltoid muscle, or by subcutaneous infusion in abdominal wall.
• Use in combination with a longer-acting insulin or basal insulin analog.
• If mixing with NPH human insulin, draw insulin glulisine into syringe first and administer prescribed dose immediately after mixing. Do not mix with insulin products other than NPH.
• Do not dilute or mix with any other insulin when used in an external insulin pump for subcutaneous infusion.
• Administer prescribed dose within 15 min before a meal or within 20 min after starting a meal.
• For subcutaneous, continuous subcutaneous infusion, or IV administration. Not for intradermal, IM, or intra-arterial administration.
• When administered IV, product is equipotent to human insulin (ie, 1 unit of insulin glulisine has same glucose-lowering effect as 1 unit of regular human insulin).
• For IV administration; do not mix with other insulins.
• For IV administration only; dilute with sodium chloride 0.9% (normal saline).

• Insulin lispro
• Replace the infusion set (reservoir syringe, tubing, and catheter) and insulin lispro Disetronic D-Tron or D-Tron plus cartridge adaptor in the external insulin pump and select a new infusion site every 48 h or less.
• In the D-Tron or D-Tron plus pump, insulin lispro 3 mL cartridges may be used for up to 7 days; replace infusion set and change infusion site every 48 h or less.
• Do not expose the external insulin pump to temperatures above 98.6°F
• For subcutaneous injection or subcutaneous infusion only. Not for intradermal, IM, IV, or intra-arterial administration.
• Do not administer if particulate matter, cloudiness, or discoloration is noted, or if solution has become viscous.
• Use in combination with a longer-acting insulin when used in patients with type 1 diabetes.
• Administer dose into abdominal wall, deltoid, or thigh. Rotate injection sites within the same region.
• Administer prescribed dose immediately (within 15 min) before a meal.
• If mixing insulin lispro with longer-acting insulin (eg, Humulin N ), draw insulin lispro into syringe first and then administer prescribed dose immediately after mixing.
• Follow manufacturer's guidelines if diluting insulin lispro.
• Can be used alone when administered by subcutaneous infusion using external insulin pump.
• Place infusion catheter in abdominal wall. Rotate infusion sites within the same region.
• Do not mix or dilute insulin lispro with any other insulin or solution when used in an external insulin pump for subcutaneous infusion.

Storage/Stability

Insulin aspart, insulin lispro

Store unopened vials, cartridges, pens, and prefilled syringes in refrigerator between 36° and 46°F until expiration date, or at room temperature below 86°F for up to 28 days. Do not freeze. Store opened vials below 86°F for up to 28 days. May be refrigerated. Store punctured cartridges, pens, or prefilled syringes below 86°F for up to 28 days. Do not refrigerate. Do not expose to excessive heat or sunlight. Humalog 3 mL cartridge used in the D-Tron or D-Tron plus should be discarded after 7 days, even if it still contains Humalog . For insulin aspart mix, store vials in refrigerator between 36° and 46°F or below 86°F for up to 28 days. Do not freeze. Protect from heat and light. Store unpunctured cartridges and prefilled syringes between 36° and 46°F. Protect from light. Store punctured cartridges and prefilled syringes below 86°F for up to 14 days. Do not refrigerate. Protect from direct heat and light.

Insulin aspart mix (eg, 70/30)

Store unopened vials and pens in refrigerator (36° to 46°F). Protect from freezing. Do not use if frozen. Vial in use can be stored outside refrigerator at temperatures below 86°F and away from direct heat and light, but discard any unused insulin after 28 days. Pens in use must not be stored in refrigerator. Pens in use can be used for 14 days if stored at room temperature (below 86°F).

Insulin detemir

Store unopened vials, cartridges, and prefilled syringes in refrigerator (36° to 46°F) until expiration date, or for up to 42 days at room temperature (below 86°F). Store in-use vials in refrigerator or at room temperature (below 86°F) for up to 42 days. Store in-use cartridges or prefilled syringes at room temperature for up to 42 days. Do not store in-use cartridges or prefilled syringes in refrigerator or with needle in place. Protect all doseforms from freezing, direct heat, and direct light. Discard if frozen. Discard 42 days after first use.

Insulin glargine

Do not store in freezer or allow to freeze. Discard if frozen. Unopened vial, cartridge system, and disposable device should be stored in refrigerator, between 36° and 46°F. Opened vials, whether refrigerated or not, must be used within 28 days. Store open vials below 86°F. Protect from direct heat and light. Opened cartridge system in OptiClik should not be refrigerated, but should be kept at room temperature (below 86°F), away from direct heat and light; discard after 28 days. Opened disposable insulin device should not be refrigerated, but should be stored below 86°F, away from direct heat and light. Discard after 28 days.

Insulin glulisine

Store unopened vials, pens, and cartridge system between 36° and 46°F. Protect from light and freezing. Discard if frozen. Store opened vials and cartridge system between 36° and 46°F or at room temperature (below 77°F), and protect from direct heat and light. Discard 28 days after opening. Do not store opened cartridges inserted in OptiClik or opened pens in refrigerator. Store below 77°F and discard 28 days after first use. Do not store insulin delivery device for cartridges in refrigerator at any time. Discard infusion sets (eg, catheter, reservoirs, tubing) and insulin glulisine in reservoir after no more than 48 h of use, or after exposure to temperatures above 98.6°F. Infusion bags are stable at room temperature for 48 h.

Insulin lispro mix 50/50, insulin lispro mix 75/25

Store unopened vials in the refrigerator between 36° and 46°F, or at room temperature (below 86°F) for 28 days. Do not freeze. Protect from direct heat and light. Store unopened pens in the refrigerator between 36° and 46°F until expiration date, or at room temperature (below 86°F) for 10 days. Protect from direct heat and light. Store opened vials below 86°F for 28 days. May be refrigerated, but do not freeze. Store opened pens below 86°F for 10 days. Do not refrigerate. Protect from direct heat and light.

Drug Interactions

ACE inhibitors (eg, captopril), angiotensin II receptor blocking agents (eg, losartan), disopyramide, fenfluramine, fenugreek, fibrates, fluoxetine, MAOIs (eg, phenelzine), octreotide, oral hypoglycemic agents, Panax ginseng, pentoxifylline, propoxyphene, salicylates, sulfa antibiotics

May increase hypoglycemic effects of insulin. Closely monitor blood glucose concentrations and adjust the insulin dose as needed.

Alcohol, beta-blockers (eg, propranolol), clonidine, lithium salts

May potentiate or weaken the blood glucose–lowering effects of insulin. Closely monitor blood glucose concentrations and adjust the insulin dose as needed.

Atypical antipsychotics, corticosteroids, danazol, diazoxide, diuretics, estrogens, glucagon, hormonal contraceptives, isoniazid, niacin, phenothiazines, protease inhibitors, somatropin, sympathomimetic agents (eg, albuterol, epinephrine, terbutaline), thyroid hormone (eg, levothyroxine)

May decrease hypoglycemic effects of insulin. Closely monitor blood glucose concentrations and adjust the insulin dose as needed.

Beta-blockers (eg, propranolol), clonidine, guanethidine, reserpine

Signs of hypoglycemia may be reduced or absent.

Pentamidine

May cause hypoglycemia, which may be followed by hyperglycemia. Closely monitor blood glucose concentrations and adjust the insulin dose as needed.

Potassium-lowering medications (eg, diuretics), medications sensitive to serum potassium concentrations

Insulin may cause a shift of potassium from the extracellular to intracellular space, possibly resulting in hypokalemia. The risk of hypokalemia may be increased. Use with caution. Closely monitor serum potassium.

Adverse Reactions

CNS

Acute painful peripheral neuropathy, asthenia, headache, neuropathy, seizure, sensory disturbances.

Dermatologic

Lipoatrophy, lipodystrophy (from repeated insulin injection into same site), lipohypertrophy, pruritus, rash, skin disorder.

EENT

Diabetic retinopathy, nasopharyngitis, ophthalmologic refraction disorder, worsening of diabetic retinopathy.

GI

Abdominal pain, diarrhea, nausea.

Genitourinary

Dysmenorrhea, sodium retention, UTI.

Hypersensitivity

Hypersensitivity reaction (including anaphylaxis, angioedema, elevated alkaline phosphatase, fast pulse, hypotension, rash, shortness of breath, sweating), insulin antibody production.

Lab Tests

Elevated alkaline phosphatase.

Local

Catheter occlusions, infusion-site reactions, itching at injection site, redness, swelling.

Metabolic-Nutritional

Hypoglycemia, hypokalemia, weight gain.

Respiratory

Bronchitis, increased cough, pharyngitis, rhinitis, upper respiratory tract infection.

Miscellaneous

Accidental injury, chest pain, fever, flu syndrome, hyporeflexia, infection, influenza, myalgia, onychomycosis, pain, peripheral edema, surgical procedure.

Precautions

Monitor Check blood sugar frequently and observe for signs of hypoglycemia and hyperglycemia. Check potassium levels closely when administering IV. Periodically measure hemoglobin A 1c to monitor long-term glycemic control. Check urine for ketones in patients at risk of ketoacidosis and observe for signs and symptoms of ketoacidosis (eg, drowsiness, frequent urination, fruit-like breath, thirst).

Pregnancy

Category B (insulin aspart, insulin lispro, insulin lispro mix); Category C (insulin aspart mix, insulin detemir, insulin glargine, insulin glulisine).

Lactation

Undetermined.

Children

Safety and efficacy not established (insulin aspart mix, insulin lispro mix). Safety and efficacy not established in children younger than 6 y with type 1 diabetes (insulin glargine, insulin detemir). Safety and efficacy not established in children younger than 4 y with type 1 diabetes (insulin glulisine). Approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump (insulin lispro) in children 3 y and older and (insulin aspart) for children 2 y and older.

Elderly

Effects of age on onset have not been determined (insulin aspart, insulin aspart mix, insulin lispro, insulin lispro mix). The initial dose, dose increments, and maintenance dosage should be conservative (insulin detemir, insulin glargine, insulin glulisine). Use caution when making dose selection, usually starting at the lower end of the dosing range, reflecting comorbidity and the greater frequency of decreased hepatic and renal function. Hypoglycemia may be difficult to recognize in elderly patients.

Hypersensitivity

Severe, life-threatening generalized allergy, including anaphylaxis, can occur.

Renal Function

Dose may need to be reduced.

Hepatic Function

Absorption or disposition is not affected; however, adjust dose as needed.

Antibody production

May occur (insulin aspart, insulin glulisine, insulin lispro).

Changing insulin

Changes in strength, brand, type, species source, or method of manufacture (rDNA vs animal source) of insulin may necessitate dosage adjustment. Any change should be made cautiously and under medical supervision.

Edema

May cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Hypoglycemia

Most common adverse reaction of insulin therapy; may result from excessive insulin dose, missed or reduced meal, or increased work or exercise without eating.

Hypokalemia

May occur. Use with caution in patients who are fasting, have abnormal neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium levels.

Intercurrent conditions

Insulin requirements may need to be altered during illness, emotional disturbances, or other stresses.

Local reactions

Redness, swelling, or itching may occur at site of injection.

Systemic allergy

May occur (uncommon).

Overdosage

Symptoms

Coma, hypoglycemia, hypokalemia, neurologic impairment, seizures.

Patient Information

• Educate patient or caregiver regarding diabetes and its management, including target ranges for blood sugar control. Instruct patient that insulin is not a substitute for diet and exercise, and to continue to follow prescribed regimens.
• Educate patient or caregiver regarding potential long-term complications of diabetes and need for regularly scheduled general physical and eye examinations.
• Advise patient or caregiver to read patient information leaflet before using the first time, and to read and check for new information each time the medication is refilled.
• Ensure that patient or caregiver understands how to store, prepare, and administer the insulin dose(s), and how to dispose of used equipment and supplies.
• Advise patient using pen or cartridge administration system to read the patient information leaflet and User Manual for the pen or cartridge before using the first time, and to read and check for new information each time medication is refilled.
• Ensure that patient using external insulin pump has read both the patient package insert for the insulin they are using and the pump manufacturer's manual. Ensure patient understands how and when to rotate infusion sites, how to program the infusion pump, how to evaluate infusion pump for malfunction, and has a plan of action in the event of infusion pump malfunction.
• Advise patient using external insulin pump to keep extra insulin available for direct subcutaneous administration in the event of a pump malfunction.
• Advise patient to continuously rotate injection sites (abdomen, thigh, upper arm) to prevent or reduce severity of injection-site reactions (eg, inflammation, lipodystrophy, pain).
• Caution patient not to inject or place infusion catheter into skin sites that are red or itchy, or show signs of lipodystrophy.
• Ensure patient or caregiver understands how to use home glucose monitor and has a plan for monitoring and recording blood sugar measurements (eg, log). Advise patient to take log to each visit with health care provider.
• Educate patient regarding value of periodic HbA _1c testing to confirm level of glucose control.
• Advise patient that dose(s) of insulin will usually be adjusted based on the results of home glucose HbA _1c monitoring.
• Ensure patient with type 1 diabetes understands how to monitor for ketones and has a plan of action in case ketones are detected.
• Review symptoms of hypoglycemia (low blood sugar) and hyperglycemia (high blood sugar), as well as action plans to undertake in the event either occurs.
• Advise patient to discuss with health care provider a plan for managing each of the following situations: insulin dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting), accidental administration of too little or too much insulin, missed insulin dose, inadequate food intake or a skipped meal, travel across time zones, change in physical activity.
• Advise patient with diabetes to carry medical identification (eg, card, bracelet) indicating their condition.
• Instruct patient to notify health care provider if experiencing severe, continuous, or frequent hypoglycemic episodes; hypoglycemic episodes with few or no warning symptoms; continuous or severe hyperglycemia; or injection-site reactions that do not go away after a few days or continue to occur.

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