NOVOLOG (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NOVOLOG. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 units/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is unknown.

NOVOLOG was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

13.2 Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of NOVOLOG has the same glucose-lowering effect as one unit of regular human insulin.

14 CLINICAL STUDIES

14.1 Overview of Clinical Studies

The safety and effectiveness of subcutaneous NOVOLOG were compared to regular human insulin in 596 type 1 diabetes adult, 187 pediatric type 1 diabetes, and 91 adult type 2 diabetes patients using NPH as basal insulin (see Tables 3, 4, 5). The reduction in glycated hemoglobin (HbA1c ) was similar to regular human insulin.

The safety and effectiveness of NOVOLOG administered by continuous subcutaneous insulin infusion (CSII) by external pump were compared to buffered regular human insulin (administered by CSII), to lispro (administered by CSII) and compared to NOVOLOG injections and NPH injection. Overall, the reduction in HbA1c was similar to the comparator.

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

Type 1 Diabetes – Adults (see Table 3)

Two 24-week, open‑label, active-controlled studies were conducted to compare the safety and efficacy of NOVOLOG to regular human insulin injection in adult patients with type 1 diabetes. Because the two study designs and results were similar, data are shown for only one study (see Table 3).

The mean age of the trial population was 39 years and mean duration of diabetes was 15.7 years. Fifty-one percent were male. Ninety-four percent were Caucasian, 2% were Black and 4% were Other. The mean BMI was approximately 25.6 kg/m2.

NOVOLOG was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c were comparable for the two treatment regimens in this study (Table 3).

Table 3. Type 1 Diabetes Mellitus – Adult (NOVOLOG plus NPH insulin vs. regular human insulin plus NPH insulin)

NOVOLOG + NPH

(n=596)

Regular Human Insulin+ NPH

(n=286)

Baseline HbA1c (%)*

7.9 ±1.1

8.0 ± 1.2

Change from Baseline HbA1c (%)

-0.1 ± 0.8

0.0 ± 0.8

Treatment Difference in HbA1c , Mean (95% confidence interval)

-0.2 (-0.3, -0.1)

*Values are Mean ± SD

Type 1 Diabetes – Pediatric (see Table 4)

The efficacy of NOVOLOG to improve glycemic control in pediatric patients with type 1 diabetes mellitus is based on an adequate and well-controlled trial of regular human insulin in pediatric patients with type 1 diabetes mellitus (Table 4). This 24-week, parallel-group study of pediatric patients with type 1 diabetes (n = 283), aged 6 to 18 years, compared two subcutaneous multiple-dose treatment regimens: NOVOLOG (n=187) or regular human insulin (n=96). NPH insulin was administered as the basal insulin. Similar effects on HbA1c were observed in both treatment groups (Table 4).

Subcutaneous administration of NOVOLOG and regular human insulin have also been compared in pediatric patients with type 1 diabetes (n=26) aged 2 to 6 years with similar effects on HbA1c .

Table 4. Pediatric Subcutaneous Administration of NOVOLOG in Type 1 Diabetes (24 weeks; n=283)

NOVOLOG + NPH

(n=187)

Regular Human Insulin+ NPH

(n=96)

Baseline HbA1c (%)*

8.3 ± 1.2

8.3 ± 1.3

Change from Baseline HbA1c (%)

0.1± 1.0

0.1± 1.1

Treatment Difference in HbA1c, Mean (95% confidence interval)

-0.2 (-0.5, 0.1)

*Values are Mean ± SD

14.3 Clinical Studies in Adults with Type 2 Diabetes with Subcutaneous Injections

Type 2 Diabetes — Adults (see Table 5)

One six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of NOVOLOG to regular human insulin in patients with type 2 diabetes (Table 5).

The mean age of the trial population was 56.6 years and mean duration of diabetes was 12.7 years. Sixty-three percent were male. Seventy-six percent were Caucasian, 9% were Black and 15% were Other. The mean BMI was approximately 29.7 kg/m2.

NOVOLOG was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c were comparable for the two treatment regimens.

Table 5. Subcutaneous NOVOLOG Administration in Type 2 Diabetes (6 months; n=176)

NOVOLOG + NPH

(n=90)

Regular Human Insulin + NPH

(n=86)

Baseline HbA1c (%)*

8.1 ± 1.2

7.8 ± 1.1

Change from Baseline HbA1c (%)

-0.3 ± 1.0

-0.1 ± 0.8

Treatment Difference in HbA1c, Mean (95% confidence interval)

– 0.1 (-0.4, 0.1)

*Values are Mean ± SD

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