BASAGLAR Solution for injection Kwikpen / Tempo pen Ref.[10756] Active ingredients: Insulin glargine

The pharmacodynamic profile for BASAGLAR was determined after subcutaneous administration of a single 0.5 U/kg dose in a euglycemic clamp study conducted in 91 healthy subjects. The median time to maximum effect of BASAGLAR (measured by the peak rate of glucose infusion) was approximately 12.0 hours. The pharmacodynamic profile of BASAGLAR following subcutaneous injection demonstrated sustained glucose lowering activity over 24 hours with no pronounced peak. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) and maximum glucose infusion rate were 1670 mg/kg and 2.12 mg/kg/min, respectively.

A euglycemic clamp study in 20 patients with type 1 diabetes showed a similar pharmacodynamic profile with a sustained glucose lowering activity over 24 hours following a single 0.3 U/kg subcutaneous dose of BASAGLAR.

After subcutaneous injection of 0.3 units/kg of another insulin glargine product, 100 units/mL, in patients with type 1 diabetes, the duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar.

The time course of action of insulins, including insulin glargine, may vary between individuals and within the same individual.

Absorption and Bioavailability

The pharmacokinetic profile for BASAGLAR was determined after subcutaneous administration of a single 0.5 U/kg dose in a euglycemic clamp study conducted in 91 healthy subjects. The insulin serum concentrations indicated a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak.

The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The mean observed area under the serum insulin concentration-time curve from time zero to 24 hours and peak serum insulin concentration were 1720 pmol*hr/L and 103 pmol/L, respectively.

Metabolism and Elimination

After subcutaneous injection of another insulin glargine product, 100 units/mL, in diabetic patients, insulin glargine is metabolized at the carboxyl terminus of the Beta chain with formation of two active metabolites M1 (21 ^A-Gly-insulin) and M2 (21 ^A-Gly-des-30 ^B-Thr-insulin). The in vitro activity of M1 and M2 were similar to that of insulin.

Specific Populations

Age, Race, and Gender

Effect of age, race, and gender on the pharmacokinetics of BASAGLAR has not been evaluated.

Obesity

Effect of BMI on the pharmacokinetics of BASAGLAR has not been evaluated.

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.

14.1 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 (HbA_1c) 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 HbA_1c 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 HbA_1c 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 HbA_1c. Observed HbA_1c 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.

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 HbA_1c (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):

14.2.122 SPL UNCLASSIFIED SECTION

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 HbA_1c (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):

14.3 Clinical Studies in Adults with Type 2 Diabetes

Patients with type 2 diabetes participated in a double-blind, active-controlled study to evaluate the glucose lowering effect of once-daily BASAGLAR plus oral antidiabetic medication (OAM) compared to that 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) administered once-daily along with OAMs. Patients were either insulin naïve (approximately 60%) and had failed to achieve adequate glycemic control on at least 2 OAMs, or were already on another insulin glargine product, 100 units/mL, or a non-U.S.-approved insulin glargine product, 100 units/mL, along with at least 2 OAMs with adequate or inadequate glycemic control (approximately 40%). A total of 759 patients were randomized. Three patients randomized to BASAGLAR did not receive study drug and were not included in efficacy analysis. The average age was approximately 59 years. The majority of patients were White (78%) and 50% of the patients were male. Sixty-eight percent of patients had GFR>90 mL/min/1.73m². The mean BMI was approximately 32 kg/m². At week 24, treatment with BASAGLAR provided a mean reduction in HbA_1c that was non-inferior to that achieved with comparator insulin glargine products, 100 units/mL (see Table 10).

Table 10. Type 2 Diabetes Mellitus – Adult (BASAGLAR plus Oral Antidiabetic Medications versus Comparator Insulin Glargine Products, 100 units/mL, plus Oral Antidiabetic Medications):

^a Three patients randomized to BASAGLAR did not receive study drug and were 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, sulfonylurea use and time of baseline basal insulin injection (daytime or evening/bedtime) as fixed effects and baseline HbA_1c 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 HbA_1c. Observed HbA_1c data at 24 weeks were available from 331 (88%) and 329 (87%) subjects randomized to the BASAGLAR and comparator insulin glargine products, 100 units/mL, groups, respectively.

In a randomized, controlled clinical study (Study E) (n=570), another insulin glargine product, 100 units/mL, was evaluated for 52 weeks in combination with oral anti-diabetic medications (a sulfonylurea, metformin, acarbose, or combination of these drugs). The average age was 59.5 years. The majority of patients were Caucasian (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m². The mean duration of diabetes was 10.3 years. This other insulin glargine product administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA_1c and fasting glucose (see Table 11). The rate of hypoglycemia was similar in this other insulin glargine product and NPH insulin treated patients [see Adverse Reactions (6.1)].

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 another insulin glargine product, 100 units/mL, 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. The average age was 59.3 years. The majority of patients were Caucasian (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m². The mean duration of diabetes was 13.7 years. This other insulin glargine product had similar effectiveness as either once- or twice daily NPH insulin in reducing HbA_1c and fasting glucose (see Table 11) with a similar incidence of hypoglycemia [see Adverse Reactions (6.1)].

In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 years of treatment with another insulin glargine product, 100 units/mL, once-daily or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of this other insulin glargine product 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 this other insulin glargine product 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 ETDRS scale. HbA_1c 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 this other insulin glargine product and NPH insulin doses to a target fasting plasma glucose ≤100 mg/dL. After this other insulin glargine product or NPH insulin dose was adjusted, other anti-diabetic agents, including pre-meal insulin were to be adjusted or added. The average age was 55.1 years. The majority of patients were Caucasian (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m². The mean duration of diabetes was 10.8 years. This other insulin glargine product group had a smaller mean reduction from baseline in HbA_1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in this other insulin glargine product group (see Table 11). Both treatment groups had a similar incidence of reported symptomatic hypoglycemia. The incidence of severe symptomatic hypoglycemia in the ORIGIN Trial is given in Table 5 [see Adverse Reactions (6.1)].

Table 11. Type 2 Diabetes Mellitus – Adult (Another Insulin Glargine Product, 100 units/mL, versus NPH):

14.3.123 SPL UNCLASSIFIED SECTION

Another Insulin Glargine Product, 100 units/mL, Timing of Daily Dosing (see Table 12)

The safety and efficacy of this other insulin glargine product 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. The average age was 40.9 years. All patients were Caucasian (100%) and 53.7% were male. The mean BMI was approximately 25.3 kg/m². The mean duration of diabetes was 17.3 years. This other insulin glargine product administered at different times of the day resulted in similar reductions in HbA_1c compared to that with bedtime administration (see Table 12). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of this other insulin glargine product regardless of time of administration.

In this study, 5% of patients in this other insulin glargine product-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 this other insulin glargine product 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. The average age was 60.8 years. The majority of patients were Caucasian (96.6%) and 53.7% were male. The mean BMI was approximately 28.7 kg/m². The mean duration of diabetes was 10.1 years. This other insulin glargine product given before breakfast was at least as effective in lowering HbA_1c as this other insulin glargine product given at bedtime or NPH insulin given at bedtime (see Table 12).

Table 12. Type 1 Diabetes Mellitus – Adults (Another Insulin Glargine Product, 100 units/mL, plus Insulin Lispro) and Type 2 Diabetes Mellitus – Adults (Another Insulin Glargine Product, 100 units/mL, plus Glimepiride versus NPH plus Glimepiride):

^a Intent to treat.
^b Total number of patients evaluable for safety.
^c Not applicable.

Five-year Trial Evaluating the Progression of Retinopathy

Retinopathy was evaluated in clinical studies with another insulin glargine product, 100 units/mL, by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for this other insulin glargine product and NPH insulin treatment groups were similar for patients with type 1 and type 2 diabetes.

Another insulin glargine product, 100 units/mL, was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA_1c was 8.4%. The primary outcome was progression by 3 or more steps on the ETDRS scale at study endpoint. Patients with pre-specified post-baseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressions regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and Intent-to-Treat populations, and indicate similarity of this other insulin glargine product to NPH in the progression of diabetic retinopathy as assessed by this outcome.

Table 13. Number (%) of Patients with 3 or More Step Progression on ETDRS Scale at Endpoint:

^a Difference = another insulin glargine product, 100 units/mL – NPH.
^b Using a generalized linear model (SAS GENMOD) with treatment and baseline HbA_1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function.

The ORIGIN Study

The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of another insulin glargine product, 100 units/mL, to standard care on major adverse cardiovascular outcomes in 12,537 participants ≥50 years of age with abnormal glucose levels [i.e., impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] or early type 2 diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.

The objective of the trial was to demonstrate that use of this other insulin glargine product could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two co-primary composite cardiovascular endpoints were used in ORIGIN. The first co-primary endpoint was the time to first occurrence of a major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction and nonfatal stroke. The second co-primary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.

Participants were randomized to either this other insulin glargine product (N=6264) titrated to a goal fasting plasma glucose of ≤95 mg/dL or to standard care (N=6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black. The median baseline BMI was 29 kg/m². Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA_1c (SD) at baseline was 6.5% (1.0). Fifty nine percent of participants had had a prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.

Vital status was available for 99.9% and 99.8% of participants randomized to this other insulin glargine product and standard care respectively at end of trial. The median duration of follow-up was 6.2 years [range: 8 days to 7.9 years]. The mean HbA_1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in this other insulin glargine product and standard group respectively. The median dose of this other insulin glargine product at end of trial was 0.45 U/kg. Eighty-one percent of patients randomized to this other insulin glargine product were using this other insulin glargine product at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in this other insulin glargine group than in the standard care group.

Overall, the incidence of major adverse cardiovascular outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups.

Table 14. Cardiovascular Outcomes in ORIGIN – Time to First Event Analyses:

In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer in the ORIGIN trial (see Table 15) was similar between treatment groups.

Table 15. Cancer Outcomes in ORIGIN – Time to First Event Analyses: