INSULIN LISPRO KWIKPEN U-100 (Generic for ADMELOG SOLOSTAR)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Administer insulin lispro 100 mg/mL and insulin lispro-aabc 100 mg/mL by subcutaneous injection or intravenous infusion only. Do not administer by intramuscular injection.
-Humalog U-200 and Lyumjev U-200 insulins are for subcutaneous injection only; do NOT give intravenously or by intramuscular injection.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections that are unusually viscous, cloudy, or discolored.
-Patients using insulin vials should never share needles or syringes with another person.

Insulin Pens:
-Insulin lispro and insulin lispro-aabc are available in 2 concentrations as a prefilled pen: 100 units/mL and 200 units/mL.
-It is essential that clinicians and patients ensure that the correct concentration of insulin lispro is used. Inadvertent use of the 200 units/mL concentration could result in severe overdose and hypoglycemia.
-Insulin pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials instead, if available, or, reserve the use of any pen for 1 patient only.
-Ensure that the patient knows how to use the type of pen needles being dispensed.-For standard pen needles with both an outer cover and an inner needle cover, remove both covers before use.
-For the safety pen needle, remove only the outer cover; the fixed inner needle shield remains in place.

-Insulin should never be withdrawn from an insulin pen cartridge.
Intravenous Administration
Continuous IV Infusion
Humalog and Admelog
-Administer insulin lispro intravenously under medical supervision; use insulin lispro 100 units/mL only to prepare intravenous infusions.
-Do NOT administer Humalog 200 units/mL intravenously.
-Rapid-acting insulins, including insulin lispro 100 units/mL and regular insulin, are equally suited for IV therapy for the treatment of diabetic ketoacidosis and the control of diabetes during surgical procedures.
-Close monitoring of blood glucose and potassium concentrations are required to avoid hypoglycemia and hypokalemia.
-Dilute insulin lispro with 0.9% Sodium Chloride Injection to a final concentration of 0.1 unit/mL to 1 unit/mL.
-Do not mix with any other insulins, drugs, or solutions.
-Storage of Humalog infusion: Infusion bags are stable when stored in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F) for 48 hours and then may be used at room temperature for up to an additional 48 hours.
-Storage of Admelog infusion: Infusion bags are stable when stored in a refrigerator between 2 and 8 degrees C (36 and 46 degrees F) for 24 hours and then may be used at room temperature for up to 4 hours.

Lyumjev
-Administer insulin lispro-aabc intravenously under medical supervision; only use insulin lispro-aabc 100 units/mL to prepare intravenous infusions.
-Do NOT administer Lyumjev 200 units/mL intravenously.
-Rapid-acting insulins, including insulin lispro-aabc 100 units/mL and regular insulin, are equally suited for IV therapy for the treatment of diabetic ketoacidosis and the control of diabetes during surgical procedures.
-Close monitoring of blood glucose and potassium concentrations is required to avoid hypoglycemia and hypokalemia.
-Dilute insulin lispro-aabc with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a final concentration of 1 unit/mL.
-Do not mix with other insulins, drugs, or solutions.
-Storage of Lyumjev infusion: Infusion bags may be stored up to 4 days when refrigerated between 2 and 8 degrees C (36 and 46 degrees F) until time of use. The same solution may be stored up to 12 hours at room temperature between 20 and 25 degrees C (68 and 77 degrees F).

Subcutaneous Administration
Intermittent Subcutaneous Injection
-Preferably, administer Humalog or Admelog shortly before a meal (i.e., meal starts within 15 minutes after injection) or immediately after a meal.
-Administer Lyumjev insulin (insulin lispro-aabc) at the start of a meal or within 20 minutes after starting a meal.
-Insulin lispro and insulin lispro-aabc are available in a multi-dose vial and 3 mL cartridges for use in various insulin pen devices (see specific product labeling). In an effort to minimize insulin wastage, some experts suggest the use of the 3 mL cartridges for children receiving small doses of insulin. However, once any insulin has been withdrawn from a cartridge using a syringe, that cartridge should not be used in an insulin pen device because the inadvertent introduction of air into the cartridge can alter the pen's mechanics resulting in inaccurate dosing.

Dilution
Humalog and Admelog:
-Insulin lispro (Humalog U-100) may be diluted to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50) using Sterile Diluent for Humalog.
-Insulin lispro (Admelog U-100) may be diluted to a concentration of 1:2 (equivalent to U-50) using Sterile 0.9% Sodium Chloride Injection.
-Do not dilute insulin lispro contained within cartridges. The cartridge should not be refilled with insulin of any type, including insulin lispro.
-Storage of diluted Humalog U-100: Insulin lispro diluted to U-10 or U-50 using Sterile Diluent for Humalog may be stored for up to 28 days at 5 degrees C (41 degrees F) and for 14 days at 30 degrees C (86 degrees F).
-Storage of diluted Admelog U-100: Insulin lispro diluted to U-50 using Sterile 0.9% Sodium Chloride Injection may be stored for up to 24 hours under refrigeration between 2 and 8 degrees C (36 and 46 degrees F) and for up to 4 hours at room temperature.

Administration
-Subcutaneous injections of insulin lispro are usually made into the anterior and lateral aspects of the thigh, the upper arms, buttocks, or the abdomen.
-Rotate injection sites within the same region with each injection to prevent lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring.

Insulin Lispro Pens:
-Humalog KwikPens and Tempo Pen:

--The needle should remain in the skin for at least 5 seconds to ensure complete delivery of the insulin dose.
-The Humalog U-100 and U-200 KwikPens and the U-100 Tempo Pen dial doses in 1 unit increments and deliver a maximum dose of 60 units per injection.
-Humalog Junior KwikPen dials doses in 0.5 unit increments and delivers a maximum dose of 30 units per injection.
-Do NOT perform dose conversion when using either the Humalog U-100 or U-200 KwikPens; the dose window shows the number of insulin units to be delivered and no conversion is needed.
-Do NOT transfer Humalog U-200 from the KwikPen to a syringe. The markings on an insulin syringe will not measure a dose of Humalog U-200 correctly and overdosage/severe hypoglycemia may result.
-Storage: Once in use, the cartridges or pens should be stored at room temperature [up to 30 degrees C (86 degrees F)] only; do NOT refrigerate. Keep away from heat and light. Once removed from refrigeration discard within 28 days, even if not opened and even if the pens or cartridges still contain insulin.


-Admelog SoloStar Pen:

--The needle should remain in the skin for at least 10 seconds to ensure complete delivery of the insulin dose.
-The Admelog pen dials doses in 1 unit increments and delivers a maximum dose of 80 units per injection.
-Storage: Once in use, pens should be stored at room temperature [below 30 degrees C (86 degrees F)] only; do not refrigerate. Keep away from heat and light. Once removed from refrigeration, cartridges and pens should be discarded within 28 days, even if they have not been opened and even if they still contain insulin.


-Lyumjev KwikPens and Tempo Pen:
--The needle should remain in the skin for at least 5 seconds to ensure complete delivery of the insulin dose.
-The Lyumjev U-100 and U-200 KwikPens and the U-100 Tempo Pen dial doses in 1 unit increments and deliver a maximum dose of 60 units per injection.
-Lyumjev Junior KwikPen dials doses in 0.5 unit increments and delivers a maximum dose of 30 units per injection.
-Do NOT perform dose conversion when using either the Lyumjev U-100 or U-200 prefilled pens; the dose window shows the number of insulin units to be delivered and no conversion is needed.
-Do NOT transfer Lyumjev U-200 from the prefilled pen to a syringe. The markings on an insulin syringe will not measure a dose of Lyumjev U-200 correctly and overdosage/severe hypoglycemia may result.
-Storage: Once in use, the cartridges or pens should be stored at room temperature [up to 30 degrees C (86 degrees F)] only; do NOT refrigerate. Keep away from heat and light. Once removed from refrigeration discard within 28 days, even if not opened and even if the pens or cartridges still contain insulin.


Insulin Lispro Vial:
-Insulin lispro (Humalog U-100) may be mixed with NPH human insulin only; however, do NOT mix Humalog U-200 with any other insulins or diluents. When mixing insulin lispro and NPH human insulin together in a syringe, draw insulin lispro into the syringe first. This prevents contamination of the remaining insulin lispro in the vial by the NPH insulin.
-Do not mix Admelog or Lyumjev (insulin lispro-aabc) with any other insulins.
-Do not mix any insulin with insulin lispro while contained within cartridges. The cartridge should not be refilled with insulin of any type, including insulin lispro.
-The product labeling for insulin glargine (Lantus) states that it should not be diluted or mixed with any other insulin; however, limited data suggest that mixing insulin glargine with insulin lispro (Humalog U-100) does not affect glycemic control or rates of hypoglycemia in children with type 1 diabetes mellitus. In these studies, the insulins were mixed immediately before injection. Cloudiness upon mixing was noted, but neither pain upon injection nor clogging of the needle was reported.
-Storage of opened vials: May refrigerate or store at room temperature [below 30 degrees C (86 degrees F)] once opened. Do not freeze. Keep away from heat and light. Vials must be used within 28 days or be discarded, even if they still contain insulin.

Continuous Subcutaneous Insulin Infusion (CSII)
Preparation and Pump Selection
-Do not mix insulin lispro with other insulins or diluents when using an external pump.
-Do NOT administer Humalog U-200 or Lyumjev U-200 using a continuous subcutaneous infusion pump.
-Follow recommendations available from the specific manufacturer of insulin lispro and the specific insulin pump to be used.
-The use of Humalog U-100 is known to be compatible with the following pumps: Disetronic H-TRON plus V100, D-TRON, and D-Tronplus with Disetronic Rapid infusion sets; MiniMed models 506, 507, and 508; and Polyfin infusion sets. Before using a pump not included in this list, consult the pump label and confirm compatibility.
-For Admelog and Lyumjev U-100 solutions, refer to the pump user manual to confirm compatibility.

Administration
Humalog and Admelog
-Rotate the infusion site within the same general region at least every 3 days. A new injection site should be selected if a current site becomes erythematous, pruritic, or thickened as skin reactions or alterations in absorption can occur. Such changes in skin surrounding an infusion site should be reported to a healthcare provider.
-For Admelog, change the insulin lispro in the reservoir (or the insulin-containing cartridge) at least every 7 days or according to the pump user manual, whichever is shorter, or after exposure to temperatures exceeding 37 degrees C (98.6 degrees F). Change the infusion set according to the manufacturer's user manual.
-For Humalog, change the insulin lispro in the reservoir (or the insulin-containing cartridge) at least every 7 days or according to the pump user manual, whichever is shorter, or after exposure to temperatures exceeding 37 degrees C (98.6 degrees F). Change the infusion set according to the manufacturer's user manual.
-Storage in continuous subcutaneous pumps: Insulin used in continuous subcutaneous pumps that is exposed to temperatures higher than 37 degrees C (98.6 degrees F) should be discarded. The temperature of the insulin may exceed ambient temperature when the pump housing, tubing, or case is exposed to sunlight or radiant heat. When insulin lispro is maintained in a pump system for longer than recommended or at high temperatures, pump malfunction, loss of metacresol (preservative), and insulin degradation may occur.

Lyumjev
-Rotate the infusion site within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis. A new infusion site should be selected if a current site becomes erythematous, pruritic, or thickened as skin reactions or alterations in absorption can occur. Such changes in the skin surrounding an infusion site should be reported to a health care provider.
-Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
-Storage in continuous subcutaneous pumps: Change the insulin lispro-aabc in the reservoir (or the insulin lispro-aabc-containing cartridge) at least every 9 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 37 degrees C (98.6 degrees F).

Hypoglycemia is the most common adverse reaction to insulin therapy; educate patients and caregivers about the prevention and management of hypoglycemia. Severe hypoglycemia was reported in 1.1% of pediatric patients with type 1 DM who received insulin lispro-aabc at mealtime. Because individual patients have different thresholds, there is no single numerical definition for hypoglycemia; however, in clinical practice, a blood glucose of less than 70 mg/dL is a standard threshold for treatment in pediatric patients. Patients experiencing symptoms of hypoglycemia should be immediately given simple carbohydrate to raise blood glucose. Mild events can be treated with 10 to 15 grams oral glucose; severe episodes can be treated with IV dextrose (2 to 3 mL/kg dextrose 10%) or IM/subcutaneous glucagon (0.5 to 1 mg depending on age/weight). Also, patients should ingest a full snack or meal shortly after that to prevent recurrence of hypoglycemia. Infants and young children are at greater risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate prediction of insulin requirements. In addition, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Physical activity also increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Less stringent A1C goals (e.g., less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia or hypoglycemia unawareness. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. The incidence of hypoglycemia is difficult to estimate because definitions of hypoglycemia in clinical trials vary. The rate of severe hypoglycemia is thought to be 5 to 20 per 100 patient-years in children. While this rate has declined over the last decade, it is still higher than that of adults. Signs and symptoms of hypoglycemia can include hunger, pallor, nauseousness or vomiting, fatigue, sweating, head pain, palpitations, numbness of the mouth, tingling in the fingers, tremor, muscle weakness, blurred vision, confusion, tachycardia, and shallow breathing. In young children, behavioral symptoms such as irritability, sudden mood changes, crying for an unknown reason, and clumsiness may be the main presenting symptoms. In severe cases, seizures and loss of consciousness can occur and require emergency treatment. Prolonged hypoglycemia can result in irreversible brain damage and even death. Using insulin analogs rather than traditional human insulin may carry a lower risk of hypoglycemia in some patients; insulin analogs, both rapid-acting (insulin aspart, insulin glulisine, and insulin lispro) and basal insulin analogs (insulin detemir and insulin glargine), have been associated with a decreased incidence of hypoglycemia in clinical trials.

Insulin therapy facilitates the intracellular uptake of potassium; therefore, hypokalemia can occur. If left untreated, hypokalemia may cause respiratory paralysis, ventricular arrhythmias, and even death. Continuous intravenous infusions of insulin lispro (e.g., during the treatment of DKA) are highest risk for causing hypokalemia; monitor serum potassium concentrations frequently and replace potassium as appropriate. Hypokalemia risk is also increased in patients using potassium-lowering medications and in patients taking medications sensitive to serum potassium concentrations.

Insulin therapy, including treatment with insulin lispro, has been associated with weight gain; this has been attributed to the anabolic effects of insulin and the decrease of glucosuria.

As with any insulin product, long-term use of insulin lispro can cause lipodystrophy at the site of repeated insulin injections or subcutaneous infusions. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue); either of these effects can affect insulin absorption. Lipodystrophy has been reported in 0.2% patients receiving insulin lispro-aabc. During postmarketing use, cases of localized cutaneous amyloidosis at the injection site have been reported. In addition, hyperglycemia has been noted with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Rotate injection sites within the same region with each injection to prevent lipodystrophy reactions and localized cutaneous amyloidosis.

Although uncommon, localized injection site reaction, including erythema, swelling, and pruritus, has been reported with insulin lispro use. Injection site reactions occurred in 6.2% of pediatric patients treated with insulin lispro-aabc (mild in 5.7% and moderate in 0.5%) during a clinical trial; less than 0.5% of patients discontinued therapy due to the reaction. These reactions usually resolve in a few days to a few weeks, but on rare occasions, may require discontinuation of insulin lispro. If an injection site reaction occurs, ensure proper injection technique and if a skin cleansing agent is being used, consider using an alternate cleansing method; in some instances, the localized reaction may be due to improper injection technique or a reaction to the cleansing agent. Some experts no longer recommend disinfecting the injection site with alcohol unless hygiene is a problem. Localized reactions and generalized myalgia have been reported with injected metacresol, which is an excipient in insulin lispro.

Severe, life-threatening, anaphylactoid reactions, may occur with any insulin, including insulin lispro. Generalized allergy to insulin may cause whole body rash, urticaria, dyspnea, wheezing, hypotension, sinus tachycardia, or diaphoresis. Human insulin like insulin lispro appears to be the least allergenic, but may also cause reactions. Desensitization procedures may be necessary in some patients. Rash (0.5%), dermatitis (0.7%), and hypersensitivity (0.5%) have been reported in pediatric patients receiving insulin lispro-aabc.

Insulin resistance can develop in patients requiring daily insulin injections. Insulin resistance can be acute resulting from infections, surgical trauma, emotional disturbances, or other endocrine disorders. Insulin resistance can also be chronic; for patients with type 2 diabetes mellitus, insulin resistance is usually associated with obesity and related to decreased tissue sensitivity to insulin. For patients with type 1 diabetes mellitus, chronic insulin resistance is often due to increased levels of circulating anti-insulin antibodies. All exogenously administered insulins have the ability to cause anti-insulin antibodies. In clinical trials with insulin lispro, the largest increase in the amount of anti-insulin antibodies occurred in patients new to insulin therapy. Antibody levels peaked by 12 months and then declined over the remaining years of study. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding. The clinical significance of antibody formation to various insulin products is not always clear, as unpredictable changes in the pharmacokinetics and pharmacodynamics of exogenous insulin are possible in the presence of anti-insulin antibodies; however, in general, a correlation between the presence of anti-insulin antibodies with insulin dose, HbA1c, or adverse events has not been demonstrated.

Peripheral edema may occur in patients receiving insulin lispro. Sodium retention and edema are especially possible if previously poor metabolic control is improved by intensified insulin therapy.

During clinical evaluation of insulin lispro (n = 81) compared to regular insulin (n = 86) in patients with type 1 diabetes mellitus, headache (29.6% vs. 22.1%, respectively), pain (19.8% vs. 16.3%), dysmenorrhea (6.2% vs. 7%), and asthenia (7.4% vs. 8.1%) were reported. During evaluation of insulin lispro (n = 714) compared to regular insulin (n = 709) in type 2 diabetes mellitus patients, headache (11.6% vs. 9.3%, respectively), and pain (10.8% vs. 10%) were reported.

Gastrointestinal adverse events reported during clinical evaluation of insulin lispro compared to regular insulin in patients with type 1 diabetes mellitus include: nausea (6.2% vs. 15.1%, respectively), diarrhea (8.6% vs. 5.8%), and abdominal pain (7.4% vs. 8.1%).

Intensification or rapid improvement in glucose control with insulin such as insulin lispro has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Adverse reactions reported during clinical evaluation of insulin lispro compared to regular insulin in patients with type 1 DM include: flu syndrome (34.6% vs. 32.6%, respectively), pharyngitis (33.3% vs. 33.7%), rhinitis (24.7% vs. 29.1%), cough increased (17.3% vs. 17.4%), infection (13.6% vs. 20.9%), accidental injury (8.6% vs. 11.6%), fever (6.2% vs. 11.6%), bronchitis (7.4% vs. 7%), and urinary tract infection (6.2% vs. 4.7%). During evaluation of insulin lispro (n = 714) compared to regular insulin (n = 709) in type 2 DM patients, reported adverse reactions include: infection (10.1% vs. 7.6%, respectively), pharyngitis (6.6% vs. 8.2%), rhinitis (8.1% vs. 6.6%), and flu syndrome (6.2% vs. 8.2%). In a clinical trial with insulin lispro-aabc in pediatric patients with type 1 DM, naso-pharyngitis was reported in 8.2% of patients taking their dose at mealtime and 5.1% of patients taking their dose after a meal. Upper respiratory tract infection was reported in 5.4% of patients taking their dose at mealtime and 1.4% of patients taking their dose after a meal. Rhinitis (0.7%) was also reported.

Insulin lispro is contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. Minor, local sensitivity characterized by redness, swelling, or itching at the site of injection does not usually contraindicate therapy. These local reactions usually resolve in a few days, but in some cases, may require discontinuation. Insulin lispro contains m-cresol and should be avoided in patients with m-cresol hypersensitivity; localized reactions and general myalgias have been reported with the use of cresol as an injectable excipient. Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis. Severe cases, including anaphylactoid reactions, may be life threatening.

Insulin lispro is contraindicated in patients during episodes of hypoglycemia. Educate patients and caregivers on the signs and symptoms of hypoglycemia, risk factors, and management strategies. Infants and young children are at particular risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate prediction of insulin requirements. In addition, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. Physical activity increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Although the A1C target is less than 7.5% across pediatric age groups in general, less stringent goals (e.g., less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia and hypoglycemia unawareness. Changes in insulin, manufacturer, type, or method or site of administration may affect glycemic control. It is essential that clinicians and patients ensure the correct insulin is dispensed and administered; this includes the correct insulin brand and concentration. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia.

A "sick-day" plan must be available for patients with diabetes to minimize the risk of DKA. Illnesses such as fever, infection, diarrhea, and vomiting can cause metabolic disturbances that alter insulin requirements; a "sick-day"' plan should instruct patients and caregivers how to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present. In addition to physical illness, thyroid disease, recent trauma or surgery, stress, emotional disturbances, and certain medications can affect insulin lispro requirements, requiring dosage adjustments.

Use insulin lispro carefully in patients who are predisposed to hypokalemia; insulin facilitates the intracellular uptake of potassium and can cause low serum potassium. Patients at risk for hypokalemia (e.g., patients who are using potassium-lowering drugs or taking potassium concentration sensitive drugs) should be monitored closely for these effects. Hypokalemia is a particular risk when insulin is given by continuous intravenous administration; monitor patients carefully. Do not use Humalog U-200 for continuous intravenous administration; use only Humalog U-100 to prepare intravenous infusions.

Patients and caregivers of those receiving insulin lispro via continuous subcutaneous insulin infusion (CSII) administration should be fully educated on the proper use and maintenance of the pump. Advise patients that self-monitoring of blood glucose is especially important when using CSII. Pump or infusion set malfunction or insulin degradation can lead to hyperglycemia and DKA or HHS in a short time because of the small subcutaneous depot of insulin. This is especially important for rapid-acting insulin analogs that are more quickly absorbed through skin and have a shorter duration of action (e.g., insulin aspart, insulin glulisine, and insulin lispro). These differences may be particularly relevant when patients are switched from multiple injection therapy or infusion with buffered regular insulin. All patients on CSII must have an alternate insulin therapy available in case of pump failure. If hyperglycemia during CSII occurs, prompt identification of the cause of hyperglycemia is necessary. Do not administer Humalog U-200 using a continuous subcutaneous infusion pump.

The effect of hepatic disease, renal impairment, or renal failure on insulin lispro dosage requirements is not clear; monitor blood glucose levels carefully in patients with changing renal or hepatic function. Some pharmacokinetic studies have shown increased circulating concentrations of insulin in patients with hepatic or renal failure; however, other data suggest no changes in insulin lispro's pharmacokinetics in these patients.

Monitor blood glucose for needed insulin lispro dosage adjustments in insulin-dependent diabetic patients whenever a change in either nicotine intake or tobacco smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose or an increase the subcutaneous absorption of insulin, respectively.

Use caution when prescribing insulin lispro to patients with compromised vision due to a potential for dosing errors. Patients with visual impairment may rely on audible clicks from insulin pens to dial their dose; preparing the injection by using audible clicks may result in dosing errors.

Description: Insulin lispro is a rapid-acting insulin analog that is produced using recombinant DNA technology. Insulin lispro differs from human insulin in that the amino acids at positions B28 and B29 (proline and lysine) are reversed. Insulin lispro is considered equipotent to regular insulin; however, it has a quicker onset of action, reaches maximum concentration faster, has less absorption variation, and has a shorter duration of action. Insulin lispro is often used as prandial or snack boluses in combination with longer-acting insulins or in external insulin pumps in children with type 1 diabetes. The use of continuous subcutaneous insulin infusion (CSII) for up to 4 years has been reported in very young children with type 1 diabetes mellitus; the use of CSII resulted in a reduction in A1C (from 7.4% to 7% at 12 months) and in the incidence of severe hypoglycemia (from 78 episodes per 100 patient-years to 37 episodes per 100 patient-years, a 53% reduction). Insulin lispro is also a treatment option for pediatric patients with type 2 diabetes who have failed to achieve or maintain glycemic goals on oral medication. Insulin lispro is FDA-approved in pediatric patients as young as 1 year of age.

General dosing information:
-Insulin lispro is a rapid-acting insulin analog equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given via intermittent subcutaneous injection.
-Insulin lispro is available in multiple concentrations. It is essential that clinicians and patients ensure that the correct concentration of insulin lispro is used. Inadvertent use of the wrong concentration could result in severe overdose and hypoglycemia or subtherapeutic dosing.
-Do NOT perform dose conversion when using either the Humalog U-100 or U-200 KwikPens; the dose window shows the number of insulin units to be delivered and no conversion is needed.

For the treatment of type 1 diabetes mellitus:
Subcutaneous dosage (Humalog or Admelog):
Children and Adolescents 3 to 17 years: 55% to 70% of the total daily insulin dose subcutaneously divided 15 minutes before or immediately after meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Subcutaneous dosage (Lyumjev):
Children and Adolescents: 55% to 70% of the total daily insulin dose subcutaneously divided 20 minutes before or at the start of meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Continuous Subcutaneous Infusion dosage (Humalog or Admelog 100 units/mL):
Children 3 to 6 years: 30% to 35% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or immediately after meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Children and Adolescents 7 to 17 years: 50% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 15 minutes before or immediately after meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Continuous Subcutaneous Infusion dosage (Lyumjev 100 units/mL):
Children 1 to 6 years: 30% to 35% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 20 minutes before or at the start of meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Children and Adolescents 7 to 17 years: 50% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 20 minutes before or at the start of meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.

For the treatment of diabetic ketoacidosis*:
Subcutaneous dosage:
Children and Adolescents: 0.15 units/kg/dose subcutaneously every 2 hours beginning at least 1 hour after the start of fluid replacement therapy. May reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours if blood glucose continues to decrease by more than 90 mg/dL despite the addition of dextrose to intravenous fluids. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated. Subcutaneous administration of rapid-acting insulin may be considered when intravenous insulin infusion is not possible and in uncomplicated mild to moderate diabetic ketoacidosis.

For the treatment of type 2 diabetes mellitus*:
Subcutaneous dosage:
Children and Adolescents: Specific dosing recommendations are not available. 0.25 to 0.5 units/kg/day of intermediate-acting or basal insulin is generally effective in achieving glycemic control and facilitating transition to metformin monotherapy. If target HbA1c is not achieved within 4 months of metformin monotherapy, consider readding basal insulin; add prandial insulin if target HbA1c is not achieved on combination metformin and basal insulin (up to 1.5 units/kg).

Therapeutic Drug Monitoring:
-Individualize glycemic goals based on the risk-benefit assessment.
-Monitor post-prandial glucose concentrations if there is an inconsistency between pre-prandial glucose and A1C concentrations and to help assess basal-bolus regimens.

Blood glucose goals for children and adolescents with type 1 diabetes :-Pre-prandial = 70 to 130 mg/dL
-Post-prandial = 90 to 180 mg/dL
-Bedtime/overnight = 80 to 140 mg/dL
-Prior to exercise = 126 to 180 mg/dL

A1C goals for children and adolescents with type 1 diabetes :-Assess A1C every 3 months in most patients or more frequently as clinically indicated.
-In general, the A1C target is less than 7% across all pediatric age groups. A lower goal of less than 6.5% is reasonable if it can be achieved without excessive hypoglycemia, negative impacts on well-being, undue burden of care, or in those who have nonglycemic factors that decrease A1C (e.g., lower erythrocyte life span) or during the honeymoon phase. A less stringent A1C goal of less than 7.5% may be appropriate for patients with a history of hypoglycemia unawareness; patients who can't articulate hypoglycemia symptoms; lack access to analog insulins, advanced insulin delivery technology, and/or continuous glucose monitors; cannot check blood glucose regularly; or have nonglycemic factors that increase A1C (e.g., high glycators). A goal of less than 8% is appropriate for patients with a history of severe hypoglycemia, limited life expectancy, or where the harms of treatment are greater than the benefits.

A1C goals for children and adolescents with type 2 diabetes :
-Assess A1C every 3 months in most patients or more frequently as clinically indicated.
-In general, the A1C target is less than 7%. A lower goal of less than 6.5% is reasonable if it can be achieved without excessive hypoglycemia or adverse effects of treatment. Appropriate patients may include those with a short duration of diabetes and lesser degrees of beta-cell dysfunction and individuals treated with lifestyle or metformin only who achieve significant weight improvement. A less stringent A1C goal of less than 7.5% may be appropriate for patients with an increased risk of hypoglycemia.

Maximum Dosage Limits:
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of blood glucose and other clinical parameters in all patient populations.

Patients with Hepatic Impairment Dosing
Some studies have noted increased circulating levels of human insulin in patients with hepatic failure. Specific dosage adjustment recommendations are not available; carefully monitor blood glucose concentrations and adjust insulin dosage as needed.

Patients with Renal Impairment Dosing
Some studies have noted increased circulating levels of human insulin in patients with renal failure; insulin requirements may be reduced. Specific dosage adjustment recommendations are not available; carefully monitor blood glucose concentrations and adjust insulin dosage as needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Endogenous insulin regulates carbohydrate, fat, and protein metabolism by several mechanisms; in general, insulin promotes the storage and inhibits the breakdown of glucose, fat, and amino acids. Insulin lowers glucose concentrations by facilitating the uptake of glucose in muscle and adipose tissue and by inhibiting hepatic glucose production (glycogenolysis and gluconeogenesis). Insulin also regulates fat metabolism by enhancing the storage of fat (lipogenesis) and inhibiting the mobilization of fat for energy in adipose tissues (lipolysis and free fatty acid oxidation). Finally, insulin is involved in the regulation of protein metabolism by increasing protein synthesis and inhibiting proteolysis in muscle tissue.

Diabetes mellitus type 1 is caused by insulin deficiency while diabetes mellitus type 2 is caused by a combination of insulin deficiency and resistance. Biosynthetic insulin and insulin analogs are used to regulate glucose metabolism in patients with diabetes mellitus. Insulin administration also enables these patients to replete their liver glycogen stores and to convert glycogen to fat. Insulin lispro is prepared using recombinant DNA technology (utilizing a non-pathogenic laboratory strain of E. coli bacteria). After subcutaneous administration, insulin lispro has a faster onset and a shorter duration of action compared to regular insulin.

Pharmacokinetics: Insulin lispro is administered by intermittent subcutaneous injection, continuous subcutaneous infusion via external SC insulin infusion pump, and via intravenous infusion. Endogenous insulin distributes widely throughout the body. A small portion is inactivated by peripheral tissues, but the majority is metabolized by the liver and kidneys.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous (IV) administration, insulin lispro and regular human insulin have similar dose-dependent clearance.

Subcutaneous Route
After subcutaneous administration, insulin lispro has a faster absorption time, faster onset of action, and shorter duration of action than regular human insulin. Insulin lispro begins to lower blood glucose after about 15 to 30 minutes; it reaches mean peak plasma concentrations in about 30 to 90 minutes when given subcutaneously. Insulin lispro has a duration of action of roughly 3 to 5 hours. After subcutaneous administration in adults, the apparent half-life of insulin lispro is 1 hour compared with 1.5 hours for regular insulin. After abdominal administration, insulin lispro concentrations are higher and duration of action is slightly shorter than after injections into the deltoid or thigh regions.


-Special Populations
Hepatic Impairment
In adult patients with type 2 diabetes and hepatic impairment, there were no noted pharmacokinetic differences from those with normal hepatic function. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver failure; therefore, careful monitoring is warranted in patients with hepatic impairment.

Renal Impairment
In adult patiens with type 2 diabetes and varying degrees of renal impairment, no differences in the pharmacokinetics of regular insulin and insulin lispro were noted. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal failure; therefore, careful monitoring is warranted in patients with renal impairment.