July 5, 2015
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Humalog

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Insulin is a hormone that is produced by certain cells in the pancreas called beta cells. Insulin helps the body use blood glucose (a type of sugar) for energy. When we e"...

Humalog




CLINICAL PHARMACOLOGY

Mechanism Of Action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. 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.

Pharmacodynamics

HUMALOG has been shown to be equipotent to human insulin on a molar basis. One unit of HUMALOG has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that HUMALOG has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

The time course of action of insulin and insulin analogs, such as HUMALOG, may vary considerably in different individuals or within the same individual. The parameters of HUMALOG activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see WARNINGS AND PRECAUTIONS].

Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa.

Blood Glucose Levels After Subcutaneous Injection - - Illustration

aBaseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

Intravenous Administration of HUMALOG U-100

The glucose lowering effect of intravenously administered HUMALOG was tested in 21 patients with type 1 diabetes. For the study, the patients' usual doses of insulin were held and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three hours run-in phase. The run-in phase was followed by a 6-hour assessment phase. During the assessment phase, patients received intravenous HUMALOG at an initial infusion rate of 0.5 units/hour. The infusion rate of HUMALOG could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.

The mean blood glucose levels during the assessment phase for patients on HUMALOG therapy are summarized below in Table 4. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with HUMALOG. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for HUMALOG.

Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of HUMALOG U-100

Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenousa
0 224 ± 16
30 205 ± 21
60 195 ± 20
120 165 ± 26
180 140 ± 26
240 123 ± 20
300 120 ± 27
360 122 ± 25
aResults shown as mean ± SD

The pharmacodynamics of a single 20 unit dose of HUMALOG U-200 administered subcutaneously were compared to the pharmacodynamics of a single 20 unit dose of HUMALOG U-100 administered subcutaneously in a euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 g and 126 g for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 h (0.5 h – 6.3 h) and 2.4 h (0.5 h – 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively.

Pharmacokinetics

Absorption and Bioavailability

Studies in healthy volunteers and patients with diabetes demonstrated that HUMALOG is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of HUMALOG ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes (see Figure 3).

Figure 3: Serum HUMALOG and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or HUMALOG (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa.

Serum HUMALOG and Insulin Levels After Subcutaneous Injection - Illustration

aBaseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

HUMALOG U-100 was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After HUMALOG was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of HUMALOG is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.

The results of a study in healthy subjects demonstrated that HUMALOG U-200 is bioequivalent to HUMALOG U-100 following administration of a single 20 unit dose.

The mean observed area under the serum insulin concentration-time curve from time zero to infinity was 2360 pmol hr/L and 2390 pmol hr/L for HUMALOG U-200 and HUMALOG U-100, respectively. The corresponding mean peak serum insulin concentration was 795 pmol/L and 909 pmol/L for HUMALOG U-200 and HUMALOG U-100, respectively. The median time to maximum concentration was 1.0 hour for both formulations.

Distribution

W hen administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of HUMALOG appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). Metabolism — Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of HUMALOG is identical to that of regular human insulin.

Elimination

After subcutaneous administration of HUMALOG, the t½ is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, HUMALOG and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, HUMALOG demonstrated a mean t½ of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t½ was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.

Specific Populations

The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of HUMALOG have not been studied.

Renal Impairment Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and HUMALOG. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with renal dysfunction.

Hepatic Impairment Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of HUMALOG as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including HUMALOG, may be necessary in patients with hepatic dysfunction.

Animal Toxicology And/Or Pharmacology

In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.

Clinical Studies

The safety and efficacy of HUMALOG U-100 were studied in children, adolescent, and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722).

Type 1 Diabetes – Adults And Adolescents

A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of HUMALOG (n=81) compared with Humulin® R [REGULAR insulin human injection, USP (rDNA origin)] (n=86). HUMALOG was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® U [ULTRALENTE® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2-to 4-week run-in period with Humulin R and Humulin U before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of HUMALOG and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group.

Table 5: Type 1 Diabetes Mellitus – Adults and Adolescents

Treatment Duration Treatment in Combination with: 12 months Humulin U
HUMALOG Humulin R
N 81 86
Baseline HbA1c (%)a 8.2 ± 1.4 8.3 ± 1.7
Change from baseline HbA1c (%)a -0.1 ± 0.9 0.1 ± 1.1
Treatment Difference in HbA1c Mean (95% confidence interval) 0.4 (0.0, 0.8)
Baseline short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1
End-of-Study short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1
Change from baseline short-acting insulin dose (units/kg/day) 0.0 ± 0.1 0.0 ± 0.1
Baseline Body weight (kg) 72 ± 12.7 71 ± 11.3
Weight change from baseline (kg) 1.4 ± 3.6 1.0 ± 2.6
Patients with severe hypoglycemia (n, %)b 14 (17%) 18 (21%)
aValues are Mean ± SD
bSevere hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.

Type 2 Diabetes – Adults

A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of HUMALOG for 3 months followed by Humulin R for 3 months or the reverse sequence. HUMALOG was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2-to 4week run-in period with Humulin R and Humulin N or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m². During the study, the majority of patients used Humulin N (84%) compared with Humulin U (16%) as their basal insulin. The reductions from baseline in HbA1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups (see Table 6).

Table 6: Type 2 Diabetes Mellitus — Adults

  Baseline End point
HUMALOG + Basal Humulin R + Basal
HbA1C (%)a 8.9 ± 1.7 8.2 ± 1.3 8.2 ± 1.4
Change from baseline HbA1c (%)a -0.7 ± 1.4 -0.7 ± 1.3
Short-acting insulin dose (units/kg/day)a 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2
Change from baseline short-acting insulin dose (units/kg/day)a 0.0 ± 0.1 0.0 ± 0.1
Body weight (kg)a 80 ± 15 81 ± 15 81 ± 15
Weight change from baseline 0.8 ± 2.7 0.9 ± 2.6
Patients with severe hypoglycemia (n, %)b 15 (2%) 16 (2%)
aValues are Mean ± SD
bSevere hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.

Type 1 Diabetes – Pediatric And Adolescents

An 8-month, crossover study of adolescents with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: HUMALOG or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. HUMALOG achieved glycemic control comparable to Humulin R, as measured by HbA1c (see Table 7), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of prepubescent children (n=60) with type 1 diabetes, aged 3 to 11 years, HUMALOG administered immediately before meals, HUMALOG administered immediately after meals and Humulin R administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, and incidence of hypoglycemia, regardless of treatment group.

Table 7: Pediatric Subcutaneous Administration of HUMALOG in Type 1 Diabetes

  Baseline End point
HUMALOG + NPH Humulin R + NPH
HbA1c (%)a 8.6 ± 1.5 8.7 ± 1.5 8.7 ± 1.6
Change from baseline HbA1c (%)a 0.1 ± 1.1 0.1 ± 1.3
Short-acting insulin dose (units/kg/day)a 0.5 ± 0.2 0.5 ± 0.2 0.5 ± 0.2
Change from baseline short-acting insulin dose (units/kg/day)a 0.01 ± 0.1 -0.01 ± 0.1
Body weight (kg)a 59.1 ± 13.1 61.1 ± 12.7 61.4 ± 12.9
Weight change from baseline (kg)a 2.0 ± 3.1 2.3 ± 3.0
Patients with severe hypoglycemia (n, %)b 5 (1.1%) 5 (1.1%)
Diabetic ketoacidosis (n, %) 11 (2.4%) 9 (1.9%)
aValues are Mean ± SD
bSevere hypoglycemia refers to hypoglycemia that required glucagon or glucose injection or resulted in coma.

Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion

To evaluate the administration of HUMALOG U-100 via external insulin pumps, two open-label, crossover design studies were performed in patients with type 1 diabetes. One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with HUMALOG or regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.8% to 7.2% in the HUMALOG-treated patients and from 7.8% to 7.5% in the regular human insulin-treated patients. Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either HUMALOG or buffered regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.7% to 7.4% in the HUMALOG-treated patients and remained unchanged from 7.7% in the buffered regular human insulin-treated patients. Rates of hypoglycemia were comparable between treatment groups in both studies.

Type 1 Diabetes – Pediatric Continuous Subcutaneous Insulin Infusion

A randomized, 16-week, open-label, parallel design, study of children and adolescents with type 1 diabetes (n=298) aged 4 to 18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or HUMALOG U-100 (n=100). These two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of hypoglycemia after 16 weeks of treatment (see Table 8). Infusion site reactions were similar between groups.

Table 8: Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)

  HUMALOG Aspart
N 100 198
Baseline HbA1c (%)a 8.2 ± 0.8 8.0 ± 0.9
Change from Baseline HbA1c (%) -0.1 ± 0.7 -0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval) 0.1 (-0.3, 0.1)
Baseline insulin dose (units/kg/24 hours)a 0.9 ± 0.3 0.9 ± 0.3
End-of-Study insulin dose (units/kg/24 hours)a 0.9 ± 0.2 0.9 ± 0.2
Patients with severe hypoglycemia (n, %)b 8 (8%) 19 (10%)
Diabetic ketoacidosis (n, %) 0 (0) 1 (0.5%)
Baseline body weight (kg)a 55.5 ± 19.0 54.1 ± 19.7
Weight Change from baseline (kg)a 1.6 ± 2.1 1.8 ± 2.1
aValues are Mean ± SD
bSevere hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.

Last reviewed on RxList: 6/30/2015
This monograph has been modified to include the generic and brand name in many instances.

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