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Lantus (Insulin Glargine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

LANTUS (insulin glargine [rDNA origin] injection) is a sterile solution of insulin glargine for use as a subcutaneous injection. Insulin glargine is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose-lowering agent [ ]. LANTUS is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, insulin glargine is 21 -Gly-30 a-L-Arg-30 b-L-Arg-human insulin and has the empirical formula C H N O S and a molecular weight of 6063. Insulin glargine has the following structural formula: See Clinical Pharmacology Escherichia coli A B B 267 404 72 78 6

LANTUS consists of insulin glargine dissolved in a clear aqueous fluid. Each milliliter of LANTUS (insulin glargine injection) contains 100 Units (3.6378 mg) insulin glargine.

The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.

The 3 mL cartridge presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection.

The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. LANTUS has a pH of approximately 4.

CLINICAL PHARMACOLOGY

Mechanism of Action

The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

Pharmacodynamics

Insulin glargine is a human insulin analog that has been designed to have low aqueous solubility at neutral pH. At pH 4, as in the LANTUS injection solution, insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a basal insulin.

In clinical studies, the glucose-lowering effect on a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. In euglycemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of subcutaneous insulin glargine was slower than NPH insulin. The effect profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH insulin. shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine. Figure 1

Figure 1. Activity Profile in Patients with Type 1 Diabetes

* Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values); indicative of insulin activity.

The longer duration of action (up to 24 hours) of LANTUS is directly related to its slower rate of absorption and supports once-daily subcutaneous administration. The time course of action of insulins, including LANTUS, may vary between individuals and within the same individual.

Pharmacokinetics

Absorption and Bioavailability. After subcutaneous injection of insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Serum insulin concentrations were thus consistent with the time profile of the pharmacodynamic activity of insulin glargine.

After subcutaneous injection of 0.3 Units/kg insulin glargine in patients with type 1 diabetes, a relatively constant concentration/time profile has been demonstrated. The duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar.

Metabolism. A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of insulin, M1 (21 -Gly-insulin) and M2 (21 -Gly-des-30 -Thr-insulin). Unchanged drug and these degradation products are also present in the circulation. A A B

Special Populations

Information on the effect of age, race, and gender on the pharmacokinetics of LANTUS is not available. However, in controlled clinical trials in adults (n=3890) and a controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between insulin glargine and NPH insulin. Age, Race, and Gender. [see ] Clinical Studies

The effect of smoking on the pharmacokinetics/pharmacodynamics of LANTUS has not been studied. Smoking.

The effect of pregnancy on the pharmacokinetics and pharmacodynamics of LANTUS has not been studied [ Pregnancy. see ]. Use in Specific Populations

. In controlled clinical trials, which included patients with Body Mass Index (BMI) up to and including 49.6 kg/m, subgroup analyses based on BMI did not show differences in safety and efficacy between insulin glargine and NPH insulin. Obesity 2 [see ] Clinical Studies

The effect of renal impairment on the pharmacokinetics of LANTUS has not been studied. However, some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Careful glucose monitoring and dose adjustments of insulin, including LANTUS, may be necessary in patients with renal impairment S Renal Impairment. [ee ]. Warnings and Precautions

. The effect of hepatic impairment on the pharmacokinetics of LANTUS has not been studied. 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 LANTUS, may be necessary in patients with hepatic impairment Hepatic Impairment [See ]. Warnings and Precautions

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 10 times and for the mouse approximately 5 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m. The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using a different vehicle. The relevance of these findings to humans is unknown. 2

Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames- and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).

In a combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 7 times the recommended human subcutaneous starting dose of 10 Units/day (0.008 mg/kg/day), based on mg/m, maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin. 2

CLINICAL STUDIES

The safety and effectiveness of LANTUS given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9–11), In general, the reduction in glycated hemoglobin (HbA1c) with LANTUS was similar to that with NPH insulin. The overall rates of hypoglycemia did not differ between patients with diabetes treated with LANTUS compared to NPH insulin. [See ] Adverse Reactions

(see). Type 1 Diabetes–Adult Table 11

In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A; n=585, Study B; n=534) were randomized to 28 weeks of basal-bolus treatment with LANTUS or NPH insulin. Regular human insulin was administered before each meal. LANTUS was administered at bedtime. NPH insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with LANTUS or NPH insulin. Insulin lispro was used before each meal. LANTUS was administered once daily at bedtime and NPH insulin was administered once or twice daily.

In these 3 studies, LANTUS and NPH insulin had similar effects on HbA1c (Table 11) with a similar overall rate of hypoglycemia. [See ] Adverse Reactions

Table 11: Type 1 Diabetes Mellitus–Adult
Study A Study B Study C
Treatment duration Treatment in combination with
28 weeks Regular insulin
28 weeks Regular insulin
16 weeks Insulin lispro
LANTUS NPH LANTUS NPH LANTUS NPH
Number of subjects treated 292 293 264 270 310 309
HbA1c
  Baseline HbA1c 8.0 8.0 7.7 7.7 7.6 7.7
    Adj. mean change from baseline +0.2 +0.1 -0.2 -0.2 -0.1 -0.1
      LANTUS – NPH +0.1 +0.1 0.0
      95% CI for Treatment difference (0.0; +0.2) (-0.1; +0.2) (-0.1; +0.1)
Basal insulin dose
  Baseline mean 21 23 29 29 28 28
  Mean change from baseline -2 0 -4 +2 -5 +1
Total insulin dose
  Baseline mean 48 52 50 51 50 50
  Mean change from baseline -1 0 0 +4 -3 0
Fasting blood glucose (mg/dL)
  Baseline mean 167 166 166 175 175 173
  Adj. mean change from baseline -21 -16 -20 -17 -29 -12
Body weight (kg)
  Baseline mean 73.2 74.8 75.5 75.0 74.8 75.6
  Mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5

Type 1 Diabetes–Pediatric (see). Table 12

In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a basal-bolus insulin regimen where regular human insulin was used before each meal. LANTUS was administered once daily at bedtime and NPH insulin was administered once or twice daily. Similar effects on HbA1c (Table 12) and the incidence of hypoglycemia were observed in both treatment groups. [See ] Adverse Reactions

Table 12: Type 1 Diabetes Mellitus–Pediatric
Study D
Treatment duration 28 weeks
Treatment in combination with Regular insulin
LANTUS NPH
Number of subjects treated 174 175
HbA1c
  Baseline mean 8.5 8.8
  Adj. mean change from baseline +0.3 +0.3
    LANTUS – NPH 0.0
    95% CI for Treatment difference (-0.2; +0.3)
Basal insulin dose
  Baseline mean 19 19
  Mean change from baseline -1 +2
Total insulin dose
  Baseline mean 43 43
  Mean change from baseline +2 +3
Fasting blood glucose (mg/dL)
  Baseline mean 194 191
  Adj. mean change from baseline -23 -12
Body weight (kg)
  Baseline mean 45.5 44.6
  Mean change from baseline 2.2 2.5

Type 2 Diabetes–Adult (see). Table 13

In a randomized, controlled clinical study (Study E) (n=570), LANTUS was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). LANTUS administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 13). The rate of hypoglycemia was similar in LANTUS and NPH insulin treated patients. [See ] Adverse Reactions

In a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral anti-diabetic medications (n=518), a basal-bolus regimen of LANTUS once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. LANTUS had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 13) with a similar incidence of hypoglycemia. [See ] Adverse Reactions

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with once-daily LANTUS or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of LANTUS or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started LANTUS at a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the LANTUS and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL. After the LANTUS or NPH insulin dose was adjusted, other anti-diabetic agents, including pre-meal insulin were to be adjusted or added. The LANTUS group had a smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the LANTUS group (Table 13). Both treatment groups had a similar incidence of reported symptomatic hypoglycemia. The incidences of severe symptomatic hypoglycemia are given in Table 6. [See ] Adverse Reactions

Table 13: Type 2 Diabetes Mellitus–Adult
Study E Study F Study G
Treatment duration 52 weeks 28 weeks 5 years
Treatment in combination with Oral agents Regular insulin Regular insulin
LANTUS NPH LANTUS NPH LANTUS NPH
Number of subjects treated 289 281 259 259 513 504
HbA1c
  Baseline mean 9.0 8.9 8.6 8.5 8.4 8.3
  Adj. mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8
    LANTUS – NPH -0.1 +0.2 +0.2
    95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1, +0.4)
Basal insulin dose 1
  Baseline mean 14 15 44.1 45.5 39 44
  Mean change from baseline +12 +9 -1 +7 +23 +30
Total insulin dose
  Baseline mean 14 15 64 67 48 53
  Mean change from baseline +12 +9 +10 +13 +41 +40
Fasting blood glucose (mg/dL)
  Baseline mean 179 180 164 166 190 180
  Adj. mean change from baseline -49 -46 -24 -22 -45 -44
Body weight (kg)
  Baseline mean 83.5 82.1 89.6 90.7 100 99
  Adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7 4.8

1 In Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5).

LANTUS Timing of Daily Dosing (see). Table 14

The safety and efficacy of LANTUS administered pre-breakfast, pre-dinner, or at bedtime were evaluated in a randomized, controlled clinical study in patients with type 1 diabetes (study H, n=378). Patients were also treated with insulin lispro at mealtime. LANTUS administered at different times of the day resulted in similar reductions in HbA1c compared to that with bedtime administration (see). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of LANTUS regardless of time of administration. Table 14

In this study, 5% of patients in the LANTUS-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of LANTUS administered pre-breakfast or at bedtime were also evaluated in a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral anti-diabetic therapy. All patients in this study also received glimepiride 3 mg daily. LANTUS given before breakfast was at least as effective in lowering HbA1c as LANTUS given at bedtime or NPH insulin given at bedtime (see). Table 14

Table 14: LANTUS Timing of Daily Dosing in Type 1 (Study H) and Type 2 (Study I) Diabetes Mellitus
Study H Study I
Treatment duration 24 weeks 24 weeks
Treatment in combination with: Insulin lispro Glimepiride
LANTUS Breakfast
LANTUS Dinner
LANTUS Bedtime
LANTUS Breakfast
LANTUS Bedtime
NPH Bedtime
**total number of patients evaluable for safety
Number of subjects treated Intent to treat 112 124 128 234 226 227
HbA1c
  Baseline mean 7.6 7.5 7.6 9.1 9.1 9.1
  Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8
Basal insulin dose (U)
Baseline mean 22 23 21 19 20 19
  Mean change from baseline 5 2 2 11 18 18
Total insulin dose (U) NA Not applicable NA NA
Baseline mean 52 52 49
  Mean change from baseline 2 3 2
Body weight (kg)
  Baseline mean 77.1 77.8 74.5 80.7 82 81
  Mean change from baseline 0.7 0.1 0.4 3.9 3.7 2.9

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