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|Insulin Analogs

Insulin Analogs

Trade Names:
NovoLog
- Injection 100 units/mL human insulin aspart (rDNA)

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

Trade Names:
Levemir
- Injection 100 units/mL insulin detemir (rDNA)

Trade Names:
Lantus
- Injection 100 units/mL insulin glargine (rDNA)

Trade Names:
Apidra
- Injection 100 units/mL insulin glulisine (rDNA)

Trade Names:
Humalog
- Injection 100 units/mL human insulin lispro (rDNA)

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

Trade Names:
Humalog Mix 50/50
- Injection 100 units/mL human insulin lispro (rDNA)

Mechanism of Action

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

Absolute bioavailability is 60%.

Absolute bioavailability is 70%.

Absolute bioavailability is 55% to 77%.

Distribution

0% to 9% bound to plasma proteins.

98% bound to albumin.

Elimination

Cl is 1.22 L/hr/kg. The t _½ is 81 min.

The t _½ is 8 to 9 hr.

The t _½ is 5 to 7 hr (dose dependent). Vd is 0.1 L/kg.

The t _½ is 42 min. Vd is 13L.

The t _½ is 1 hr. Vd is 0.26 to 0.36 L/kg.

Peak

1 to 3 hr.

1 to 4 hr.

6 to 8 hr.

55 min.

0.5 to 1.5 hr.

Duration

3 to 5 hr.

5.7 to 23.2 hr (dose dependent).

24 hr.

Special Populations

Higher insulin detemir AUC levels in elderly because of reduced Cl.

Indications and Usage

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

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

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

Contraindications

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

Dosage and Administration

Subcutaneous Individualize dose (usual requirement 0.5 to 1 units/kg/day). Insulin pump When used in the external insulin infusion pump, the initial pump programming is based on the total insulin dose of the previous regimen. Although there is interpatient variability, approximately 50% of the total dose is given as meal-related boluses and the remainder as basal infusion. IV infusion Possible under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia.

Subcutaneous Variable; generally administered bid.

Subcutaneous Change basal insulin to insulin detemir on a unit-to-unit basis then adjust to achieve glycemic targets.

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

Subcutaneous Start with 10 units daily and adjust according to patients needs; total daily dose ranges from 2 to 100 units. When transferring from once-daily neutral protamine Hagedorn (NPH) human insulin or ultralente human insulin to once-daily insulin glargine, initiate insulin glargine at 10 units daily. When transferring from bid NPH human insulin to insulin glargine, reduce initial insulin glargine dose by 20% (compared with total daily NPH dose), and then adjust based on patient response.

Subcutaneous Individualize dose. External infusion pump Individualize dose.

Subcutaneous Individualize dose. Insulin pump Individualize dose.

Subcutaneous Variable; generally administered bid.

General Advice

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

• 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.

• 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 ΙΙ , 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.
• For IV infusion, add prescribed dose of insulin aspart to 0.9% sodium chloride, 5% dextrose, or 10% dextrose with 40 mmol/L potassium chloride, using polypropylene infusion bags. Final concentration should contain 0.05 to 1 units of insulin aspart/mL.

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

• For subcutaneous injection only. Not to be administered intradermal, IM, IV, intra-arterially, or by insulin infusion pump.
• Do not administer if particulate matter, cloudiness, or discoloration 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.

• For subcutaneous or external infusion pump only. Not for intradermal, IM, IV, or intra-arterial administration.
• 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 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.
• Used in combination with a longer-acting insulin when used in patients with type 1 diabetes.
• May be used without a longer-acting insulin when used in combination with a sulfonylurea in patients with type 2 diabetes.
• Administer dose into abdominal wall, deltoid, or thigh. Rotate injection sites within the same region.
• Administer prescribed dose immediately (within 15 min) before or immediately after 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 aspart with any other insulin or solution when used in an external insulin pump for subcutaneous infusion.

Storage/Stability

Store unopened vials, cartridges, and prefilled syringes in refrigerator (36° to 46°F). Protect from freezing. Discard if frozen or exposed to temperature exceeding 98.6°F. Store opened vials of insulin aspart in refrigerator (36° to 46°F) or at temperature below 86°F. Do not refrigerate cartridges or prefilled syringes after first use. Discard 28 days after first use. Discard infusion sets (catheters, reservoirs, tubing) and insulin aspart in reservoir after no more than 48 hr or after exposure to temperatures greater than 98.6°F. Infusion bags are stable for up to 24 hr if stored at room temperature (below 86°F).

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

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 (36° to 46°F) 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 dose forms from freezing, direct heat, and direct light. Discard if frozen. Discard 42 days after first use.

Store unopened vials and cartridges in refrigerator (36° to 46°F). Protect from freezing. Discard vial or cartridge if frozen. Store opened vials in refrigerator (36° to 46°F) or at room temperature (below 86°F). Do not refrigerate cartridges in delivery device after first use. Store at room temperature (below 86°F) and protect from direct heat and light. Discard 28 days after first use. Do not store insulin delivery device for cartridges in refrigerator at any time.

Store unopened vials and cartridges at 36° to 46°F. Protect from light and freezing. Discard if frozen. Store opened vials at 36° to 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 in refrigerator at any time. 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 hr of use or after exposure to temperatures greater than 98.6°F.

Store unopened vials, cartridges, and prefilled syringes in refrigerator (36° to 46°F). Protect from freezing. Discard if frozen. Unopened vials, cartridges, and prefilled syringes can be stored at room temperature (below 86°F) for up to 28 days if protected from direct heat and light. Store opened vials in refrigerator (36° to 46°F) or at room temperature (below 86°F). Do not refrigerate cartridges or prefilled syringes after first use. Discard 28 days after first use. Discard infusion sets (catheters, reservoirs, tubing) and insulin lispro in reservoir after no more than 48 hr. Discard 3 mL cartridge used in D-TRON or D-TRON plus cartridge adapter after 7 days.

Store unopened pens in refrigerator (36° to 46°F). Protect from freezing. Do not use if frozen. Unopened pens also may be stored at room temperature (below 86°F) but must be used within 10 days or discarded. Pens in use must not be stored in refrigerator. Pens in use can be used for up to 10 days if stored at room temperature (below 86°F). Protect pens from direct heat and light.

Drug Interactions

May potentiate or weaken the blood glucose-lowering effects of insulin.

May increase hypoglycemic effects of insulin.

May decrease hypoglycemic effects of insulin.

Signs of hypoglycemia may be reduced or absent.

May cause hypoglycemia, which may be followed by hyperglycemia.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Dermatologic

Lipodystrophy (from repeated insulin injection into same site); pruritus; rash.

Metabolic

Hyperglycemia; hypoglycemia; hypokalemia; ketosic; weight gain.

Miscellaneous

Hypersensitivity reaction (eg, anaphylaxis, angioedema, elevated alkaline phosphate, fast pulse, hypotension, rash, shortness of breath, sweating); local reactions (eg, itching at injection site, redness, swelling).

Precautions

Pregnancy

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

Lactation

Undetermined.

Children

Safety and efficacy not established (insulin aspart mix, insulin glulisine, insulin lispro mix).

Safety and efficacy not established in children younger than 6 yr of age with type 1 diabetes.

Elderly

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 the elderly.

Renal Function

Dose may need to be reduced.

Hepatic Function

Dose may need to be reduced.

Antibody production

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

Changing insulin

Changes in strength, brand, type, species source, or method of manufacture (rDNA versus animal source) of insulin may necessitate dosage adjustment. Make changes cautiously.

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 patient who are fasting, have abnormal neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium levels (insulin aspart).

Intercurrent conditions

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

Systemic allergy

May occur (uncommon).

Overdosage

Symptoms

Hypoglycemia (including confusion, convulsions, diplopia, dizziness, headache, hunger fatigue, moist or dry skin, nausea, nervousness, numb or tingling mouth, psychosis, rapid or shallow respiration, skin pallor, unconsciousness, weakness), hypokalemia.

Patient Information

• Explain name, dose, action, potential benefits, and potential side effects of drug.
• 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 that they should 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 patient or caregiver understands how to store, prepare, and administer the insulin dose(s), and dispose of used equipment and supplies.
• Advise patient using pen or cartridge administration system to read the Information for the Patient insert and User Manual for the pen or cartridge before using the first time and to read and check for new information each time the medication is refilled.
• Ensure 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, program the infusion pump, 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 reddened, itching, 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 A _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 A _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 event occurs.
• Advise patient to discuss with their 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, Medi-Alert ) indicating 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.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breastfeeding.
• Instruct patient not to take prescription or OTC drugs, dietary supplements, or herbal preparations without consulting health care provider.
• Advise patient that follow-up visits and lab tests will be necessary to monitor therapy and to keep appointments.