APIDRA SOLOSTAR

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

Route-Specific Administration

Injectable Administration
-Administer by subcutaneous injection or intravenously only. Do NOT administer 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, discolored, or contain particulate matter or clumps. Insulin glulisine is clear and colorless.
-Patients using insulin vials should never share needles or syringes with another person.

Insulin Pens:
-Insulin glulisine is available in one concentration as a prefilled pen: 100 units/mL.
-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-Insulin should never be withdrawn from an insulin pen cartridge.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
Although insulin glulisine is FDA-approved for intravenous administration, there are limited data for this route in pediatric patients with diabetes.

Continuous IV Infusion
-Rapid-acting insulins, including insulin glulisine 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 levels is required to avoid hypoglycemia and hypokalemia.
-Use with infusion systems that use polyvinyl chloride (PVC) infusion bags and PVC tubing with a dedicated infusion line.
-Dilute insulin glulisine with 0.9% Sodium Chloride injection ONLY to a final concentration of 0.05 units/mL to 1 unit/mL.
-Insulin glulisine is NOT compatible in Ringer's solution or Dextrose injection solutions. The use of other diluents, infusion bags, or tubing has not been studied.
-Storage: Infusion bags are stable at room temperature for 48 hours.

Subcutaneous Administration
Intermittent Subcutaneous Injection
-Preferably, administer insulin glulisine shortly before a meal (i.e., meal starts within 15 minutes after injection) or within 20 minutes after starting the meal.
-Double-check the insulin concentration and dosage in the syringe or injection device prior to administration. If using a pen or other injector device, prime the device prior to each injection to ensure accurate dosing.

Administration
-Subcutaneous injections of insulin glulisine are usually made into the anterior and lateral aspects of the thigh, the upper arms, 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 Glulisine Pens:
-Apidra SoloStar:
--The needle should remain in the skin for at least 10 seconds to ensure complete delivery of the insulin dose (the patient should slowly count to 10).
-Dials in 1 unit increments and delivers a maximum dose of 80 units per injection.
-Storage: Once in use, store pens at room temperature [below 25 degrees C (77 degrees F)] for up to 28 days; do NOT refrigerate. Once removed from refrigeration, pens should be discarded after 28 days, even if they have not been opened and even if they still contain insulin.


Insulin Glulisine Vials:
-Insulin glulisine may be mixed with NPH human insulin ONLY. Do not mix with other insulins or solutions.
-When mixing insulin glulisine and NPH human insulin together in a syringe, draw insulin glulisine into the syringe first. This prevents contamination of the remaining insulin glulisine in the vial by the NPH insulin.
-Storage of Opened Vials: May refrigerate or store at room temperature [below 25 degrees C (77 degrees F)] for up to 28 days. Do not freeze. Keep away from heat and light. Opened vials should be discarded after 28 days, even if they still contain insulin.

Continuous Subcutaneous Insulin Infusion (CSII)
Preparation and Pump Selection
-Do not mix insulin glulisine with other insulins or diluents when using in an external pump.
-Follow recommendations available from the manufacturers of insulin glulisine and the specific insulin pump to be used.
-The use of insulin glulisine is known to be compatible with the following pumps: Disetronic H-TRON plus V100 and D-TRON and MiniMed models 506, 507, 507c, and 508. Before using a pump not included in this list, consult the pump label and confirm compatibility.

Administration
-Rotate the infusion site within the same general region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. 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.
-Train patients to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure.
-Change the insulin glulisine in the reservoir at least every 48 hours or according to the pump user manual, whichever is shorter.
-Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual.
-Do not dilute or mix insulin glulisine when administering by continuous subcutaneous infusion.
-Do not expose insulin glulisine in the pump reservoir to temperatures exceeding 37 degrees C (98.6 degrees F). When insulin glulisine 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.

Headache was reported by 6.9% of pediatric patients with type 1 diabetes who received insulin glulisine compared to 11.2% of those who received insulin lispro during clinical trials. In general, headache is reported in an estimated 5-7% of patients receiving insulin based on various insulin therapy trials and may at times be related to low blood glucose.

Hypoglycemia is the most common adverse reaction to insulin therapy; educate patients and caregivers about the prevention and management of hypoglycemia. The incidence of hypoglycemia is difficult to estimate because definitions of hypoglycemia in clinical trials vary. In a 26-week phase 3 trial, severe symptomatic hypoglycemia was reported in 16.2% (45 of 277) of children and adolescents with type 1 diabetes mellitus who received insulin glulisine over 26 weeks, higher than in adult patients at 4.8% (16 of 339). Hypoglycemic seizures were reported in 6.1% of children and adolescents who received insulin glulisine compared to 4.7% of those that received insulin lispro. Because individual patients have different thresholds, there is no single numerical definition for hypoglycemia; however, in clinical practice, a blood glucose level 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 carbohydrates to raise blood glucose levels. 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 the prediction of insulin requirements. Also, 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. Signs and symptoms of hypoglycemia can include hunger, pallor, nauseousness or vomiting, fatigue, sweating, headache, 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 can cause respiratory paralysis, ventricular arrhythmias, and even death. Intravenous infusions of insulin and concomitant use of potassium-lowering medications can increase the risk of hypokalemia; monitor serum potassium concentrations as clinically indicated and replace potassium as appropriate.

Insulin therapy, including treatment with insulin glulisine, 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 glulisine 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. 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.

Localized injection site reaction, including erythema, swelling, and pruritus, has been reported with insulin glulisine use. These reactions usually resolve in a few days to a few weeks, but in rare occasions, may require discontinuation of insulin glulisine. 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 glulisine. Arthralgia has also been reported by adults taking insulin glulisine. Infusion-related issues have also been reported with the use of continuous subcutaneous infusions of insulin glulisine. In a 12-week randomized study in patients with type 1 diabetes (n = 59), the rates of subcutaneous pump catheter occlusions were similar for insulin glulisine (0.08%) and insulin aspart (0.15%) treated patients. Infusion site reactions were reported in 10.3% patients receiving insulin glulisine and 13.3% of patients receiving insulin aspart.

Severe, life-threatening, anaphylactoid reactions, may occur with any insulin, including insulin glulisine. Generalized allergy to insulin may cause whole body rash (unspecified), urticaria, dyspnea, wheezing, hypotension, sinus tachycardia, or diaphoresis. Human insulin like insulin glulisine appears to be the least allergenic, but may also cause reactions. Desensitization procedures may be necessary in some patients. During clinical trials with insulin glulisine, potential allergic reactions occurred in 4.3% of patients treated with insulin glulisine versus 3.8% of patients treated with the comparator short-acting insulin. During clinical trials, treatment with insulin glulisine was permanently discontinued in 1 of 1833 patients due to a potential systemic allergic reaction.

Insulin resistance can develop in patients requiring daily insulin injections. Insulin resistance can be acute resulting from infection, 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 a study in patients with type 1 diabetes (n = 333), the concentrations of insulin antibodies that react with both human insulin and insulin glulisine (cross-reactive insulin antibodies) remained near baseline during the first 6 months of the study in patients receiving insulin glulisine. A decrease in antibody concentration was observed during the following 6 months of the study. In a study in patients with type 2 diabetes (n = 411), a similar increase in cross-reactive insulin antibody concentration was observed in the patients receiving insulin glulisine and in the patients treated with human insulin during the first 9 months of the study. Thereafter the concentration of antibodies decreased in the patients receiving insulin glulisine and remained stable in the human insulin patients. There was no correlation between cross-reactive insulin antibody concentration and changes in HbA1C, insulin doses, or incidence of hypoglycemia. Insulin glulisine did not elicit a significant antibody response in a study of children and adolescents with type 1 diabetes. 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 taking insulin therapy like insulin glulisine. Sodium retention and edema are especially possible if previously poor metabolic control is improved by intensified insulin therapy. In pooled studies of adults with type 2 diabetes, peripheral edema was reported in 7.5% of patients receiving insulin glulisine.

Intensification or rapid improvement in glucose control with insulin glulisine 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.

In clinical studies, children and adolescent patients receiving insulin glulisine reported naso-pharyngitis (9%) and upper respiratory infection (8.3%). Adult patients also reported influenza (6.2%).

In clinical trials of adults with type 2 diabetes receiving insulin glulisine, 3.9% experienced hypertension compared to 5.3% of those receiving regular human insulin.

Insulin glulisine is contraindicated for use in patients hypersensitive to the insulin or 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 glulisine 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 glulisine 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. Less stringent A1C 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 also 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 glulisine requirements; dosage adjustments may be necessary.

Use insulin glulisine 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 given by continuous intravenous administration; monitor patients carefully.

Patients and caregivers of those receiving insulin glulisine 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.

Hepatic disease, renal impairment, or renal failure may affect insulin glulisine dosage requirements. In a study of 24 non-diabetic subjects, those with moderate or severe renal impairment had increased exposure to insulin glulisine by 29% and 40%, respectively, compared to those with normal renal function. Clearance of insulin glulisine was reduced by 20-25%. Some pharmacokinetic studies have shown increased circulating levels of insulin in patients with hepatic failure. Insulin dosage adjustments may be needed in some patients.

Monitor blood glucose for needed insulin aspart 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.. The specific effects of smoking on the pharmacokinetics or pharmacodynamics of insulin glulisine have not been studied.

Use caution when prescribing insulin glulisine 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 glulisine is a rapid-acting insulin analog that is produced using recombinant DNA technology. Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. Insulin glulisine 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 after subcutaneous administration. Compared to other rapid-acting insulins (insulin aspart and insulin lispro), less trial data are available describing the use of insulin glulisine in pediatric patients in the treatment of type 1 diabetes mellitus (DM). Some data from continuous subcutaneous insulin infusion (CSII) studies have shown a higher occlusion rate and symptomatic hypoglycemia with insulin glulisine than the other rapid-acting insulin analogs. Insulin glulisine is often used as prandial or snack boluses in combination with longer-acting insulins. Administration may also occur immediately after meals or snacks if needed, offering the ability to more accurately dose children who have erratic food intake. Insulin glulisine may also be given continuously via an external insulin pump, offering flexibility to vary basal rates and give meal- or snack-related boluses without additional needle sticks. Insulin glulisine is also a treatment option for patients with type 2 diabetes mellitus who have failed to achieve or maintain glycemic goals on oral medication. Insulin glulisine is FDA-approved in pediatric patients as young as 4 years.

For the treatment of type 1 diabetes mellitus:
Subcutaneous dosage:
Children and Adolescents 4 to 17 years: 55% to 70% of the total daily insulin dose subcutaneously divided 15 minutes before or within 20 minutes after 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:
Children 4 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 within 20 minutes after starting 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 within 20 minutes after starting 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 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 glulisine is prepared using recombinant DNA technology (utilizing a non-pathogenic laboratory strain of E. coli [K12]). Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced with lysine and the lysine in position B29 is replaced with glutamic acid. The glucose lowering activities of regular human insulin and insulin glulisine are equipotent when administered intravenously; however, after subcutaneous administration, insulin glulisine has a faster onset and a shorter duration of action compared to regular insulin.

Pharmacokinetics: Insulin glulisine is most commonly administered by intermittent subcutaneous injection or continuous subcutaneous infusion via external insulin infusion pumps; however, intravenous continuous infusions have also been used in the management of diabetic ketoacidosis (DKA). Endogenous insulin distributes widely throughout the body. After intravenous administration, the volume of distribution is similar between insulin glulisine and regular insulin. A small portion of insulin 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 administration, the distribution and elimination of insulin glulisine and regular human insulin are similar.

Subcutaneous Route
After subcutaneous administration, insulin glulisine has an onset of action of approximately 20 minutes, which is more rapid than the onset of regular insulin. Insulin glulisine reaches mean peak plasma concentrations faster (median 60 minutes) than regular insulin when given subcutaneously. The duration of action is also shorter for insulin glulisine (approximately 3 to 5 hours) compared to regular insulin. After subcutenous administration, the apparent half-life of insulin glulisine is 42 minutes.


-Special Populations
Pediatrics
Children and Adolescents 7 to 16 years
In a study of 20 children and adolescents with type 1 diabetes mellitus (T1DM), the relative differences between the pharmacokinetic and pharmacodynamic properties of insulin glulisine and regular human insulin were similar to differences observed in healthy adults and adults with T1DM.

Renal Impairment
In a small study of 24 non-diabetic adult subjects, those with moderate (CrCl 30-50 ml/min) and severe (CrCl < 30 ml/min) renal impairment had increased exposure to insulin glulisine (29-40%) and decreased clearance (20-25%) compared to subjects with normal renal function. Careful monitoring is warranted in patients with renal impairment.