BASAGLAR KwikPen (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In mice and rats, standard two-year carcinogenicity studies with another insulin glargine product 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/m2. 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.

Another insulin glargine product 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 of another insulin glargine product 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/m2 , 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.

14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

The safety and effectiveness of another insulin glargine product, 100 units/mL, 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 adults and 349 pediatric patients with type 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 8, 9, 11, and 12). In general, the reduction in glycated hemoglobin (HbA1c ) with this other insulin glargine product was similar to that with NPH insulin.

14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes

Patients with inadequately controlled type 1 diabetes participated in a 24-week open-label, active-controlled study with a 28 week extension to evaluate the glucose lowering effect of once-daily BASAGLAR compared to that of once-daily administration of another insulin glargine product, 100 units/mL, or a non-U.S.-approved insulin glargine product, 100 units/mL, (comparator insulin glargine products, 100 units/mL) both in combination with mealtime insulin lispro. Randomized were 535 adults with type 1 diabetes. Mean age was 41.2 years and mean duration of diabetes was 16.39 years. 57.9% were male. 74.5% were Caucasian, 2.1% Black or African American and 4.3% American Indian or Alaskan native. 3.9% were Hispanic. 73.5 percent of patients had GFR>90 mL/min/1.73m2. The mean BMI was approximately 25.54 kg/m2. At week 24, treatment with BASAGLAR provided a mean reduction in HbA1c that was non-inferior to that achieved with comparator insulin glargine products, 100 units/mL (see Table 7).

Table 7: Type 1 Diabetes Mellitus – Adult (BASAGLAR plus Mealtime insulin versus Comparator Insulin Glargine Products, 100 units/mL, plus Mealtime Insulin)

a One patient randomized to the BASAGLAR group was not included in the Full Analysis Set.

b “Comparator insulin glargine products, 100 units/mL” refers to another insulin glargine product, 100 units/mL, and a non-U.S.-approved insulin glargine product, 100 units/mL, used in this study.

c ANCOVA Model includes treatment, country and time of baseline basal insulin injection (daytime or evening/bedtime) as fixed effects and baseline HbA1c as covariate.

d The results were calculated based on the number of patients in the Full Analysis Set using their last observed post-baseline value of HbA1c . Observed HbA1c data at 24 weeks were available from 256 (95.5%) and 258 (96.6%) subjects randomized to the BASAGLAR and comparator insulin glargine products, 100 units/mL, groups, respectively.

Efficacy Parameter BASAGLAR + insulin lispro(N=268 a ) Comparator Insulin Glargine Products, 100 units/mL b + insulin lispro(N=267)
HbA 1c (%)
Baseline (mean) 7.75 7.79
Change from baseline (adjusted meanc,d) -0.35 -0.46
Difference from comparator (adjusted meanc,d)(95% CI) 0.11(-0.002, 0.219)
Proportion of patients achieving HbA1c <7%d 34.5% 32.2%

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 another insulin glargine product, 100 units/mL, or NPH insulin. Regular human insulin was administered before each meal. This other insulin glargine product was administered at bedtime. NPH insulin was administered once daily at bedtime or in the morning and at bedtime when used twice daily. In Study A, the average age was 39.2 years. The majority of patients were Caucasian (99%) and 55.7% were male. The mean BMI was approximately 24.9 kg/m2. The mean duration of diabetes was 15.5 years. In Study B, the average age was 38.5 years. The majority of patients were Caucasian (95.3%) and 50.6% were male. The mean BMI was approximately 25.8 kg/m2. The mean duration of diabetes was 17.4 years.

In another clinical study (Study C), patients with type 1 diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with another insulin glargine product, 100 units/mL, or NPH insulin. Insulin lispro was used before each meal. This other insulin glargine product was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39.2 years. The majority of patients were Caucasian (96.9%) and 50.6% were male. The mean BMI was approximately 25.6 kg/m2. The mean duration of diabetes was 18.5 years.

In these 3 studies, another insulin glargine product, 100 units/mL, and NPH insulin had similar effects on HbA1c (see Table 8) with a similar overall rate of hypoglycemia [see Adverse Reactions (6.1)].

Table 8: Type 1 Diabetes Mellitus – Adult (Another Insulin Glargine Product, 100 units/mL, versus NPH)
Treatment duration Treatment in combination with Study A28 weeksRegular insulin Study B28 weeksRegular insulin Study C16 weeksInsulin lispro
Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH Another Insulin Glargine Product NPH
Number of subject treated 292 293 264 270 310 309
HbA 1c (%)
Baseline (mean) 8.0 8.0 7.7 7.7 7.6 7.7
Adjusted mean change at trial end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1
Treatment Difference (95% CI) +0.1 (0.0; + 0.2) +0.1(-0.1; + 0.2) 0.0 (+0.1; + 0.1)
Fasting blood glucose (mg/dL)
Baseline (mean) 167 166 166 175 175 173
Adjusted mean change at trial end -21 -16 -20 -17 -29 -12

Type 1 Diabetes – Pediatric ( see Table 9)

The efficacy of BASAGLAR to improve glycemic control in pediatric patients with type 1 diabetes mellitus is based on an adequate and well-controlled trial of another insulin glargine product, 100 units/mL, in pediatric patients with type 1 diabetes mellitus (Study D). In this randomized, active-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. Patients were randomized to either this other insulin glargine product administered once daily at bedtime or NPH insulin administered once or twice daily. The average age was 11.7 years. The majority of patients were Caucasian (96.8%) and 51.9% were male. The mean BMI was approximately 18.9 kg/m2. The mean duration of diabetes was 4.8 years. Similar effects on HbA1c (see Table 9) were observed in both treatment groups.

Table 9: Type 1 Diabetes Mellitus – Pediatric (Another Insulin Glargine Product, 100 units/mL, plus Regular Insulin versus NPH plus Regular Insulin)
Study D
Another Insulin Glargine Product + Regular Insulin NPH + Regular Insulin
Number of subjects treated 174 175
HbA 1c
Baseline mean 8.5 8.8
Change from baseline (adjusted mean) +0.3 +0.3
Difference from NPH (adjusted mean) (95% CI) 0.0(-0.2; +0.3)
Fasting blood glucose (mg/dL)
Baseline mean 194 191
Mean change from baseline -23 -12

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