Lispro-PFC

Uses

Lispro-PFC is an insulin analogue that is used for the treatment of patients with diabetes mellitus for the control of hyperglycemia. Lispro-PFC has a more rapid onset and a shorter duration of action than human regular insulin. Therefore, in patients with type 1 diabetes, Lispro-PFC should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Lispro-PFC may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents.

Lispro-PFC 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 Lispro-PFC 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

Lispro-PFC dosage

Adult: SC Dosing regimen should be individualised and adjusted based on patient's glycaemic response. Usual range is 0.5-1 unit/kg/day.

Type 1 diabetes mellitus:Approximately one third of the total daily insulin requirements SC; rapid-acting or short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements

Usual daily maintenance range: 0.5-1 unit/kg/day in divided doses; nonobese may require 0.4-0.6 unit/kg/day; obese may require 0.8-1.2 units/kg/day

Type 2 diabetes mellitus: If inadequately controlled with oral medication: 10 units/day SC (or 0.1 -0.2 unit/kg/day) of intermediate- or long-acting insulin given at bedtime generally recommended; as an alternative, rapid-acting formulations, such as insulin lispro, given before meals have also been used; dose must be adjusted carefully.

Side Effects

Clinical studies comparing Lispro-PFC with Regular human insulin did not demonstrate a difference in frequency of adverse events between the two treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole: allergic reactions. Skin and Appendages: injection site reaction, lipodystrophy, pruritus, rash. Other: hypoglycemia.

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

Insulin requirements may be increased by medications with hyperglycemic activity such as corticosteroids, isoniazid, certain lipid-lowering drugs (e.g., niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy. Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, Angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (e.g., octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients.

Food Interaction

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. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. In patients with diabetes or gestational diabetes insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physicians if they intend to become, or if they become pregnant while taking Lispro-PFC.

Nursing Mothers: It is unknown whether insulin lispro is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when insulin lispro is administered to a nursing woman. Use of insulin lispro is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

Contraindication

Lispro-PFC is contraindicated by patients hypersensitivity to insulin lispro or the other excipients.

Special Warning

Pediatric Use: Lispro-PFC is approved for use in children for subcutaneous daily injections. Only the U-100 formulation of Lispro-PFC is approved for use in children by continuous subcutaneous infusion in insulin pumps. Lispro-PFC has not been studied in pediatric patients younger than 3 years of age. Lispro-PFC has not been studied in pediatric patients with type 2 diabetes. As in adults, the dosage of Lispro-PFC 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 Lispro-PFC, 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 Lispro-PFC action have not been performed.

Renal Impairment: Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Lispro-PFC 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 Lispro-PFC 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°C - 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.

Innovators Monograph

You find simplified version here Lispro-PFC