Insulin Glulisine [rDNA origin] Inj

Mechanism Of Action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin glulisine. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

The glucose lowering activities of APIDRA and of regular human insulin are equipotent when administered by the intravenous route. After subcutaneous administration, the effect of APIDRA is more rapid in onset and of shorter duration compared to regular human insulin. [See Pharmacodynamics].

Pharmacodynamics

Studies in healthy volunteers and patients with diabetes demonstrated that APIDRA has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

In a study in patients with type 1 diabetes (n= 20), the glucose-lowering profiles of APIDRA and regular human insulin were assessed at various times in relation to a standard meal at a dose of 0.15 Units/kg. (Figure 1.)

The maximum blood glucose excursion (ΔGLUmax; baseline subtracted glucose concentration) for APIDRA injected 2 minutes before a meal was 65 mg/dL compared to 64 mg/dL for regular human insulin injected 30 minutes before a meal (see Figure 1A), and 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1B). The maximum blood glucose excursion for APIDRA injected 15 minutes after the start of a meal was 85 mg/dL compared to 84 mg/dL for regular human insulin injected 2 minutes before a meal (see Figure 1C).

Figure 1. Serial mean blood glucose collected up to 6 hours following a single dose of APIDRA and regular human insulin. APIDRA given 2 minutes (APIDRA -pre) before the start of a meal compared to regular human insulin given 30 minutes (Regular -30 min) before start of the meal (Figure 1A) and compared to regular human insulin (Regular -pre) given 2 minutes before a meal (Figure 1B). APIDRA given 15 minutes (APIDRA -post) after start of a meal compared to regular human insulin (Regular -pre) given 2 minutes before a meal (Figure 1C). On the x-axis zero (0) is the start of a 15-minute meal.

Figure 1A

Figure 1B

Figure C

In a randomized, open-label, two-way crossover study, 16 healthy male subjects received an intravenous infusion of APIDRA or regular human insulin with saline diluent at a rate of 0.8 milliUnits/kg/min for two hours. Infusion of the same dose of APIDRA or regular human insulin produced equivalent glucose disposal at steady state.

Pharmacokinetics

Pharmacokinetic profiles in healthy volunteers and patients with diabetes (type 1 or type 2) demonstrated that absorption of insulin glulisine was faster than that of regular human insulin.

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 Units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microUnits/mL (range 40 to 131 microUnits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microUnits/mL (range 35 to 71 microUnits/mL) for regular human insulin. (Figure 2)

Figure 2. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 1 diabetes after a dose of 0.15 Units/kg.

Figure 2

Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.2 Units/kg in an euglycemic clamp study in patients with type 2 diabetes (n=24) and a body mass index (BMI) between 20 and 36 kg/m². The median time to maximum concentration (Tmax) was 100 minutes (range 40 to 120 minutes) and the median peak concentration (Cmax) was 84 microUnits/mL (range 53 to 165 microUnits/mL) for insulin glulisine compared to a median Tmax of 240 minutes (range 80 to 360 minutes) and a median Cmax of 41 microUnits/mL (range 33 to 61 microUnits/mL) for regular human insulin. (Figure 3.)

Figure 3. Pharmacokinetic profiles of insulin glulisine and regular human insulin in patients with type 2 diabetes after a subcutaneous dose of 0.2 Units/kg.

Figure 3

When APIDRA was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

In a clinical study in healthy volunteers (n=32) the total insulin glulisine bioavailability was similar after subcutaneous injection of insulin glulisine and NPH insulin (premixed in the syringe) and following separate simultaneous subcutaneous injections. There was 27% attenuation of the maximum concentration (Cmax) of APIDRA after premixing; however, the time to maximum concentration (Tmax) was not affected. No data are available on mixing APIDRA with insulin preparations other than NPH insulin. [See Clinical Studies].

The distribution and elimination of insulin glulisine and regular human insulin after intravenous administration are similar with volumes of distribution of 13 and 21 L and half-lives of 13 and 17 minutes, respectively. After subcutaneous administration, insulin glulisine is eliminated more rapidly than regular human insulin with an apparent half-life of 42 minutes compared to 86 minutes.

Clinical Pharmacology In Specific Populations

The pharmacokinetic and pharmacodynamic properties of APIDRA and regular human insulin were assessed in a study conducted in children 7 to 11 years old (n=10) and adolescents 12 to 16 years old (n=10) with type 1 diabetes. The relative differences in pharmacokinetics and pharmacodynamics between APIDRA and regular human insulin in these patients with type 1 diabetes were similar to those in healthy adult subjects and adults with type 1 diabetes.

A study in 24 healthy Caucasians and Japanese subjects compared the pharmacokinetics and pharmacodynamics after subcutaneous injection of insulin glulisine, insulin lispro, and regular human insulin. With subcutaneous injection of insulin glulisine, Japanese subjects had a greater initial exposure (33%) for the ratio of AUC(0-1h) to AUC(0-clamp end) than Caucasians (21%) although the total exposures were similar. There were similar findings with insulin lispro and regular human insulin.

Insulin glulisine and regular human insulin were administered subcutaneously at a dose of 0.3 Units/kg in a euglycemic clamp study in obese, non-diabetic subjects (n=18) with a body mass index (BMI) between 30 and 40 kg/m². The median time to maximum concentration (Tmax) was 85 minutes (range 49 to 150 minutes) and the median peak concentration (Cmax) was 192 microUnits/mL (range 98 to 380 microUnits/mL) for insulin glulisine compared to a median Tmax of 150 minutes (range 90 to 240 minutes) and a median Cmax of 86 microUnits/mL (range 43 to 175 microUnits/mL) for regular human insulin.

The more rapid onset of action and shorter duration of activity of APIDRA and insulin lispro compared to regular human insulin were maintained in an obese non-diabetic population (n= 18). (Figure 4.)

Figure 4. Glucose infusion rates (GIR) in a euglycemic clamp study after subcutaneous injection of 0.3 Units/kg of APIDRA, insulin lispro or regular human insulin in an obese population.

Figure 4

Studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. In a study performed in 24 non-diabetic subjects with normal renal function (ClCr > 80 mL/min), moderate renal impairment (30-50 mL/min) and severe renal impairment ( < 30 mL/min), the subjects with moderate and severe renal impairment had increased exposure to insulin glulisine by 29% to 40% and reduced clearance of insulin glulisine by 20% to 25% compared to subjects with normal renal function. [See WARNINGS AND PRECAUTIONS].

The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. [See WARNINGS AND PRECAUTIONS].

The effect of gender on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

The effect of smoking on the pharmacokinetics and pharmacodynamics of APIDRA has not been studied.

Clinical Studies

The safety and efficacy of APIDRA was studied in adult patients with type 1 and type 2 diabetes (n =1833) and in children and adolescent patients (4 to 17 years) with type 1 diabetes (n=572). The primary efficacy parameter in these trials was glycemic control, assessed using glycated hemoglobin (GHb reported as HbA1c equivalent).

Type 1 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA (n= 339) compared to insulin lispro (n= 333) when administered subcutaneously within 15 minutes before a meal. Insulin glargine was administered once daily in the evening as the basal insulin. There was a 4week run-in period with insulin lispro and insulin glargine prior to randomization. Most patients were Caucasian (97%). Fifty eight percent of the patients were men. The mean age was 39 years (range 18 to 74 years). Glycemic control, the number of daily short-acting insulin injections and the total daily doses of APIDRA and insulin lispro were similar in the two treatment groups (Table 6).

Table 6: Type 1 Diabetes Mellitus–Adult

Type 2 Diabetes-Adults

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in insulin-treated patients with type 2 diabetes to assess the safety and efficacy of APIDRA (n= 435) given within 15 minutes before a meal compared to regular human insulin (n=441) administered 30 to 45 minutes prior to a meal. NPH human insulin was given twice a day as the basal insulin. All patients participated in a 4-week run-in period with regular human insulin and NPH human insulin. Eighty-five percent of patients were Caucasian and 11% were Black. The mean age was 58 years (range 26 to 84 years). The average body mass index (BMI) was 34.6 kg/m². At randomization, 58% of the patients were taking an oral antidiabetic agent. These patients were instructed to continue use of their oral antidiabetic agent at the same dose throughout the trial. The majority of patients (79%) mixed their short-acting insulin with NPH human insulin immediately prior to injection. The reductions from baseline in GHb were similar between the 2 treatment groups (see Table 7). No differences between APIDRA and regular human insulin groups were seen in the number of daily short-acting insulin injections or basal or short-acting insulin doses. (See Table 7.)

Table 7: Type 2 Diabetes Mellitus–Adult

Type 1 Diabetes-Adults: Pre-And Post-Meal Administration

A 12-week, randomized, open-label, active-controlled, non-inferiority study was conducted in patients with type 1 diabetes to assess the safety and efficacy of APIDRA administered at different times with respect to a meal. APIDRA was administered subcutaneously either within 15 minutes before a meal (n=286) or immediately after a meal (n=296) and regular human insulin (n= 278) was administered subcutaneously 30 to 45 minutes prior to a meal. Insulin glargine was administered once daily at bedtime as the basal insulin. There was a 4-week run-in period with regular human insulin and insulin glargine followed by randomization. Most patients were Caucasian (94%). The mean age was 40 years (range 18 to 73 years). Glycemic control (see Table 8) was comparable for the 3 treatment regimens. No changes from baseline between the treatments were seen in the total daily number of short-acting insulin injections. (See Table 8.)

Table 8: Pre-and Post-Meal Administration in Type 1 Diabetes Mellitus–Adult

Type 1 Diabetes-Pediatric Patients

A 26-week, randomized, open-label, active-controlled, non-inferiority study was conducted in children and adolescents older than 4 years of age with type 1 diabetes mellitus to assess the safety and efficacy of APIDRA (n= 277) compared to insulin lispro (n= 295) when administered subcutaneously within 15 minutes before a meal. Patients also received insulin glargine (administered once daily in the evening) or NPH insulin (administered once in the morning and once in the evening). There was a 4-week run-in period with insulin lispro and insulin glargine or NPH prior to randomization. Most patients were Caucasian (91%). Fifty percent of the patients were male. The mean age was 12.5 years (range 4 to 17 years). Mean BMI was 20.6 kg/m² . Glycemic control (see Table 9) was comparable for the two treatment regimens.

Table 9: Results from a 26-week study in pediatric patients with type 1 diabetes mellitus

Type 1 Diabetes-Adults: Continuous Subcutaneous Insulin Infusion

A 12-week randomized, active control study (APIDRA versus insulin aspart) conducted in adults with type 1 diabetes (APIDRA n= 29, insulin aspart n=30) evaluated the use of APIDRA in an external continuous subcutaneous insulin pump. All patients were Caucasian. The mean age was 46 years (range 21 to 73 years). The mean GHb increased from baseline to endpoint in both treatment groups (from 6.8% to 7.0% for APIDRA; from 7.1% to 7.2% for insulin aspart).

Insulin glulisine is a fast-acting insulin that begins to work very quickly. You should use it within 15 minutes before or 20 minutes after you start eating a meal.

Take care to keep your blood sugar from getting too low, causing hypoglycemia. Symptoms of low blood sugar may include headache, nausea, hunger, confusion, drowsiness, weakness, dizziness, blurred vision, fast heartbeat, sweating, tremor, or trouble concentrating. Carry a piece of non-dietetic hard candy or glucose tablets with you in case you have low blood sugar. Also be sure your family and close friends know how to help you in an emergency.

Also watch for signs of blood sugar that is too high (hyperglycemia). These symptoms include increased thirst, loss of appetite, increased urination, nausea, vomiting, drowsiness, dry skin, and dry mouth. Check your blood sugar levels and ask your doctor how to adjust your insulin doses if needed.

Never share an injection pen or cartridge with another person. Sharing injection pens or cartridges can allow disease such as hepatitis or HIV to pass from one person to another.

Insulin glulisine is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Do not use this medication if you are allergic to insulin, or if you are having an episode of hypoglycemia (low blood sugar).

Before using insulin glulisine, tell your doctor if you have liver or kidney disease.

Tell your doctor about all other medications you use, including any oral (taken by mouth) diabetes medications.

Insulin glulisine is only part of a complete program of treatment that may also include diet, exercise, weight control, foot care, eye care, dental care, and testing your blood sugar. Follow your diet, medication, and exercise routines very closely. Changing any of these factors can affect your blood sugar levels.

Your doctor will need to check your progress on a regular basis. Do not miss any scheduled appointments.

FDA pregnancy category C. It is not known whether insulin glulisine is harmful to an unborn baby. Before using this medication, tell your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known whether insulin glulisine passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not change the brand of insulin glulisine or syringe you are using without first talking to your doctor or pharmacist.

Avoid drinking alcohol. Your blood sugar may become dangerously low if you drink alcohol while using insulin glulisine.

Do not expose insulin glulisine to high heat. Throw the medication away if it becomes hotter than 98 degrees F.

Your pharmacist can provide more information about insulin glulisine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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