Humalog (Insulin Lispro)

HUMALOG™

Lilly

Insulin Lispro

Antidiabetic Agent

Action And Clinical Pharmacology: Insulin lispro is a rapid-acting analogue of human insulin. Due to its quick onset of action, insulin lispro should be given within 15 minutes of a meal. Insulin lispro is created by inverting the natural Pro-Lys sequence in human insulin at positions 28 and 29 in the C terminal portion of the B-chain. This change in amino acid sequence slightly modifies the physicochemical properties of the molecule relative to native human insulin in such a manner that insulin lispro self-associates less avidly and dissociates into its monomeric form more rapidly than regular insulin. As a result, insulin lispro is absorbed more rapidly than regular soluble insulin from s.c. sites of injection and also has a shorter duration of action.

S.C. injected regular insulin typically results in serum insulin concentrations that peak later and remain elevated for a longer time than those following normal pancreatic insulin secretion in nondiabetics. When regular insulin is used to control postprandial blood glucose, adequate control is often not achieved because the amount of regular insulin needed to normalize postprandial glucose excursion often leads to late hypoglycemia. By producing more rapid and higher serum insulin concentrations with a shorter duration of activity (2 to 5 hours), insulin lispro decreases glucose excursion during and after meals with less chance for hypoglycemia.

The reversed sequence of lysine and proline in insulin lispro, is identical to that on human IGF-1’s B-chain. The incidence of self-association with IGF-1 is known to be lower than observed with human insulin. Incorporating this IGF-1-like feature into the human insulin molecule markedly changes the physicochemical behavior of insulin lispro but does not significantly alter its pharmacodynamic action because the terminal part of the B-chain does not participate in insulin’s interaction with the insulin receptor. In vitro experiments showed that insulin lispro interacts with the insulin receptor much like regular human insulin does. Although binding to the IGF-1 receptor is higher than for regular human insulin (´1.5), it is significantly less than that of IGF-1 itself (more than 1 000 times less) and does not promote cell growth in biological assays to any greater extent than human insulin.

A glucose clamp study was performed, in healthy volunteers, in which a 10 U dose of insulin lispro was compared to Humulin R. Doses were given s.c.; an additional 10 U dose of i.v. regular insulin was given as an absolute reference.

Insulin lispro showed statistically higher peak concentrations (Cmax) which occurred earlier than Humulin R (Tmax). Total absorption was comparable, with area under the curve (AUC) values of serum concentration vs time which were not statistically different

Subsequent pharmacokinetic studies in Type I patients confirmed that a significantly faster increase in serum insulin levels and a shorter plasma half-life resulted from an injection of Humalog when compared to Humulin R.

In clinical studies after 1 year, the decrease in glucose excursion during and after meals with insulin lispro was consistent, although not always significant, when compared to Humulin R. However, there was no significant difference in hemoglobin A1c levels between the 2 treatment groups. The frequency of hypoglycemia was not statistically significant in 1 year parallel studies (Humalog, n=543; Humulin R, n=561), but was significantly less with insulin lispro therapy in a 6 month crossover study in Type I patients (n=1 008) which also demonstrated a significant reduction in nocturnal hypoglycemia with insulin lispro.

Indications And Clinical Uses: For the treatment of patients with diabetes mellitus who require insulin for the maintenance of normal glucose homeostasis. Insulin lispro is also indicated for the initial stabilization of diabetes mellitus. Insulin lispro is a short-acting insulin analogue and is for use in conjunction with a longer acting human insulin.

Contra-Indications: During episodes of hypoglycemia (see Hypoglycemia in Overdose: Symptoms and Treatment) and in patients sensitive to insulin lispro or one of Humalog’s excipients.

Manufacturers’ Warnings In Clinical States: Due to its quick onset of action, insulin lispro should be given within 15 minutes of a meal.

Any change of insulin or human insulin analogue should be made cautiously and only under medical supervision. Changes in purity, strength, brand (manufacturer), type (insulin lispro, regular, NPH, lente, etc.), species (beef, pork, beef-pork, human), and/or method of manufacture (recombinant DNA vs animal source insulin) may result in the need for a change in dosage.

Precautions: General: Insulin lispro had a similar safety profile to Humulin R over the course of the clinical studies although its efficacy has not been studied in clinical trials beyond 1 year. Insulin lispro has been shown to control hemoglobin A1c levels as effectively as human insulin although there is currently no evidence that better control is obtained with long-term use.

Visual disturbances in uncontrolled diabetes due to refractive changes are reversed during the early phase of effective management. However, since alteration in osmotic equilibrium between the lens and ocular fluids may not stabilize for a few weeks after initiating therapy, it is wise to postpone prescribing new corrective lenses for 3 to 6 weeks.

A study in nondiabetic human volunteers with mild to moderate or severe to endstage renal disease showed that the clearance of both insulin lispro and Humulin R did not differ. However, there is no specific information at this time with regard to the use of insulin lispro in diabetes patients with renal impairment.

Additional adjustment of dosage may be required during intercurrent illness and/or emotional disturbances.

Transferring Patients from Other Insulins: Patients taking insulin lispro may require a change in dosage from that used with their usual insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.

A few patients who have experienced hypoglycemic reactions after transfer from animal-source insulin to human insulin have reported that the early warning symptoms of hypoglycemia were less pronounced or different from those experienced with their previous insulin. However, the counterregulatory and symptomatic (autonomic and neuroglycopenic) responses to hypoglycemia were studied and found to be superimposable for insulin lispro and regular human insulin.

Patients whose blood glucose is greatly improved, e.g., by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycemia and should be advised accordingly. Uncorrected hypoglycemic or hyperglycemic reactions can cause loss of consciousness, coma, or death.

Allergic Reaction: Prompt recognition and appropriate management of the allergic complications of insulin therapy are important for the safe and effective control of diabetes mellitus. Antibodies to insulin are frequently cross-reactive. Therefore, patients who have demonstrated an allergic reaction to other insulins may demonstrate an allergic reaction to insulin lispro. Local allergy in patients occasionally occurs as redness, swelling, and itching at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, this condition may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique. Systemic allergy may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalized allergy may be life-threatening (see Contraindications).

Pregnancy: The use of insulin lispro in pregnancy has not been studied. It is essential to maintain good glucose control in both gestational diabetes and throughout pregnancy in Type I and II patients. In insulin dependent diabetes mellitus, insulin requirements usually decrease during the first trimester and increase during the second and third trimesters.

Patients with diabetes should be advised to inform their doctor if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health is essential in pregnant patients with diabetes.

Lactation: The use of insulin lispro in nursing mothers has not been studied. Diabetic patients who are nursing may require adjustments in insulin dose and/or diet.

Drug Interactions: Drug interactions with insulin formulations including insulin lispro may include the following: Insulin requirements may be reduced in the presence of drugs with hypoglycemic activity, such as oral hypoglycemics, salicylates, sulfa antibiotics, and certain antidepressants.

Hormones that tend to counteract the hypoglycemic effects of insulin include growth hormone, corticotropin, glucocorticoids, thyroid hormone and glucagon. Epinephrine not only inhibits the secretion of insulin, but also stimulates glycogen breakdown to glucose. Thus, the presence of such diseases as acromegaly, Cushing’s syndrome, hyperthyroidism, and pheochromocytoma complicate the control of diabetes.

The hypoglycemic action of insulin may also be antagonized by phenytoin. Insulin’s hypoglycemic action can be increased in some patients by concomitant administration of anabolic steroids, MAO inhibitors, guanethidine, alcohol, propranolol (masking effect), or other drugs affecting beta-adrenergic receptors, or by daily doses of 1.5 to 6 g of salicylates.

Insulin requirements can be increased, decreased, or unchanged in patients receiving diuretics. Concomitant administration of oral contraceptives can cause a decrease in glucose tolerance in diabetic women possibly resulting in increased daily insulin requirements.

The physician should be consulted when using other medications in addition to insulin lispro.

Adverse Reactions: Rarely, administration of insulin s.c. can result in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue). If you notice either of these conditions, consult your doctor. A change in your injection technique may help alleviate the problem.

Symptoms And Treatment Of Overdose: Symptoms: With the rapid onset of activity of insulin lispro, it is important that the insulin analogue be given close to mealtime (within 15 minutes of a meal). A significant deviation could put the patient at risk of hypoglycemia.

Insulins have no specific overdose definitions because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycemia may occur as a result of an excess of insulin or insulin lispro relative to food intake and energy expenditure or in patients who have an infection or become ill (especially with diarrhea or vomiting).

Symptoms are likely to appear anytime when the blood sugar concentration falls below 3 mmol/L (50 mg/100 mL) but may occur with a sudden drop in blood glucose even when the value remains above 3 mmol/L (50 mg/100 mL).

Hypoglycemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.

Treatment: REG>Mild hypoglycemic episodes will respond to oral administration of glucose or sugar-containing foods.

Correction of moderately severe hypoglycemia can be accomplished by i.m. or s.c. administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution i.v.

Patients who are unable to take sugar orally or who are unconscious should be treated with i.v. administration of glucose at a medical facility or should be given an injection of glucagon (either i.m. or s.c.). The patient should be given oral carbohydrates as soon as consciousness is recovered.

Dosage And Administration: Although insulin lispro has a quicker onset of action and shorter duration of activity, dosing is comparable to regular human insulin. The dosage of insulin lispro, like all other insulin formulations, is dependent upon the individual patient requirements. The dose and number of insulin injections should be adjusted to maintain blood glucose concentrations as close to normal as possible.

Additional adjustment of dosage may be required in diabetes patients with renal impairment, during intercurrent illness and/or emotional disturbances.

Adjustment of dosage may also be necessary if patients undertake increased physical activity or change their usual diet.

New Patients: Patients receiving insulin for the first time can be started on insulin lispro in the same manner as they would be on animal-source or human insulin.

Patients should be monitored closely during the adjustment period.

Transfer Patients: When transferring patients to insulin lispro, use the same dose and dosage schedule. However, some patients transferring to insulin lispro may require a change in dosage from that used with their previous insulin. Analysis of a database of IDDM patients indicates that basal insulin requirements increase by 0.04 U/kg, while insulin lispro requirements decrease by 0.03 U/kg, after 1 year of treatment. For NIDDM patients both short acting and basal insulin requirements increase slightly after 1 year of treatment with both insulin lispro and Humulin R.

Changes in total daily dosage, the number of injections per day, and/or timing of injections may be necessary to achieve maximum glycemic control.

Administration: Insulin lispro is a clear, colorless solution. It is important to always examine the appearance of the vial or cartridge before withdrawing a dose. Do not use it if it is cloudy, unusually viscous or gelled, precipitated, or even slightly colored; if there are clumps floating in the liquid, or if particles appear to be sticking to the sides or bottom of the vial or cartridge.

Insulin lispro preparations should be given by s.c. injection but may, although not recommended, also be given by i.m. injection. It may also be administered i.v. under conditions where regular human insulin is given i.v.

S.C. administration, preferably by the patient, should be in the upper arms, thighs, buttocks or abdomen. When compared to Humulin R, insulin lispro retains its more rapid onset and shorter duration of action irrespective of the s.c. injection site used. Therefore, injection sites can be rotated so that the same site is not used more than approximately once a month.

Care should be taken to ensure that a blood vessel has not been entered. The injection site should not be massaged.

The effects of mixing insulin lispro with either animal-source insulins or human insulin preparations produced by other manufacturers have not been studied. This practice is not recommended.

If insulin lispro is mixed with a longer-acting insulin, it should be drawn into the syringe first to prevent clouding of the insulin lispro by the longer-acting insulin. Injection should be made immediately after mixing.

Availability And Storage: Vials of 10 mL, boxes of 1. Cartridges of 1.5 and 3 mL, boxes of 5. All in a strength of 100 units/mL. Cartridges are designed for use with B-D Pen Cartridge Systems or future Lilly injector systems. Nonmedicinal ingredients: dibasic sodium phosphate, glycerin, m-cresol and zinc. Hydrochloric acid and/or sodium hydroxide may have been added. The cartridge containing insulin lispro is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be reused. Preparations should be stored in a refrigerator between 2 and 10°C. They should not be frozen or exposed to excessive heat or sunlight. If refrigeration is not possible, the vial or cartridge being used can be kept at ambient temperature for up to 28 days, below 30°C and away from direct heat and light. Following insertion in a pen, the cartridge and pen should not be refrigerated. Do not use after expiry date on label.

HUMALOG™ Lilly Insulin Lispro Antidiabetic Agent

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