Insulin lispro protamine and insulin lispro

Uses

A mixture of 75% insulin lispro protamine suspension and 25% insulin lispro injection, (rDNA origin), is used for the treatment of patients with diabetes mellitus for the control of hyperglycemia.

A mixture of 50% insulin lispro protamine suspension and 50% insulin lispro injection, (rDNA origin), is also used for the treatment of patients with diabetes mellitus for the control of hyperglycemia.

Insulin lispro protamine and insulin lispro is also used to associated treatment for these conditions: Diabetes Mellitus, Diabetic Ketoacidosis, Gestational Diabetes Mellitus (GDM), Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus

How Insulin lispro protamine and insulin lispro works

Insulin lispro binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Reversal of the proline and lysine residues at positions B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers. Hexamers of insulin lispro are produced in the presence of zinc and m-cresol. These weakly associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting properties.

Dosage

Insulin lispro protamine and insulin lispro dosage

Combination rapid-onset (faster than regular insulin) and intermediate-acting insulins in fixed dose. Dose regimen varies among patients depending on metabolic needs; typical daily insulin requirements range between 0.5-1 unit/kg

Side Effects

Hypoglycaemia; hypokalemia, oedema; pruritus; pulpitation, nausea, rash; hypersensitivity reactions; lipoatropy or lipohypertrophy with SC Inj.

Toxicity

Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Rare cases of lipoatrophy or lipohypertrophy reactions have been observed.

Precaution

Renal or hepatic impairment; pregnancy, lactation; transferring from other insulin. Monitor serum glucose, potassium, electrolytes, HbA1c and lipid profile. Concomitant illness esp infections.

Interaction

Effects may be increased by: oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAOIs, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics. Effects may be decreased by: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents, isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, oral contraceptives, lithium. Signs of hypoglycaemia may be masked by beta-blockers, clonidine.

Volume of Distribution

When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of insulin lispro appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively).

Elimination Route

Insulin lispro is rapidly absorbed following subcutaneous administration. It is also absorbed more quickly than regular human insulin. Peak serum levels occur 30-90 minutes after injection in healthy subjects. Absorption also differs depending on the site of injection. After insulin lispro was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive. The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L and 2390 pmol hr/L for HUMALOG U-200 and HUMALOG U-100, respectively. The corresponding mean peak serum insulin concentration was 795 pmol/L and 909 pmol/L for HUMALOG U-200 and HUMALOG U-100, respectively. The median time to maximum concentration was 1.0 hour for both formulations.

Half Life

After subcutaneous administration of insulin lispro, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively).

Clearance

Clearance is dose dependent. When a dose of 0.1 unit/kg and 0.2 unit/kg were administered intravenously, the mean clearance was 21.0 mL/min/kg and 9.6 mL/min/kg respectively.

Pregnancy & Breastfeeding use

Pregnancy Category B. Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Lactation: Unknown whether distributed in breast milk; compatible with breast feeding, but lactating women may require dosage adjustment; caution advised

Contraindication

Insulin Lispro Protamine & Insulin Lispro is contraindicated during episodes of hypoglycemia and in patients sensitive to insulin lispro or any of the excipients contained in the formulation

Special Warning

Pediatric Use: Insulin Lispro is approved for use in children for subcutaneous daily injections. Only the U-100 formulation of Insulin Lispro is approved for use in children by continuous subcutaneous infusion in insulin pumps. Insulin Lispro has not been studied in pediatric patients younger than 3 years of age. Insulin Lispro has not been studied in pediatric patients with type 2 diabetes. As in adults, the dosage of Insulin Lispro must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose.

Geriatric Use: Of the total number of subjects (n=2834) in eight clinical studies of Insulin Lispro, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Insulin Lispro action have not been performed.

Renal Impairment: Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro dose adjustment and more frequent blood glucose monitoring.

Hepatic Impairment: Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro dose adjustment and more frequent blood glucose monitoring

Acute Overdose

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Storage Condition

Store at 2-8° C in a refrigerator. Do not freeze. In case of insulin for recent use need not be refrigerated, try to keep it in a cool place and keep away from heat and light. The insulin in use can be kept under the room temperature for a month.

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