he effect of pregnancy on the pharmacokinetics and pharmacodynamicsof FIASP® has not been studied [see Use in SpecificPopulations (8.1)].
Patients with Renal and Hepatic ImpairmentBased on studies conducted with insulin aspart, renal and hepaticimpairment is not known to impact the pharmacokinetics of insulin
aspart.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment ofFertilityIn 52-week studies, Sprague-Dawley rats were dosed subcutaneouslywith insulin aspart at 10, 50, and 200 units/kg/day(approximately 2, 8, and 32 times the human subcutaneous doseof 1.0 units/kg/day, based on units/body surface area, respectively).
At a dose of 200 units/kg/day, insulin aspart increased theincidence of mammary gland tumors in females when compared tountreated controls. The incidence of mammary tumors for insulinaspart was not significantly different than for regular human insulin.
The relevance of these findings to humans is not known.Insulin aspart was not genotoxic in the following tests: Ames test,mouse lymphoma cell forward gene mutation test, human peripheralblood lymphocyte chromosome aberration test, in vivo micronucleustest in mice, and in ex vivo UDS test in rat liver hepatocytes.
In fertility studies in male and female rats, at subcutaneousdoses up to 200 units/kg/day (approximately 32 times the humansubcutaneous dose, based on units/body surface area), no directadverse effects on male and female fertility, or general reproductiveperformance of animals was observed.
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies
The efficacy of FIASP® was eva luated in 3 randomized, activecontrolledtrials of 18 to 26 weeks duration. In total 1224 adultsubjects were randomized to FIASP® (N=763 with type 1diabetes; N=461 with type 2 diabetes). In adult patients with type1 diabetes, mealtime FIASP® and postmeal FIASP® led to noninferiorglycemic control compared to mealtime NovoLog®, bothin combination with insulin detemir. In adult patients with type 2diabetes, mealtime FIASP® provided non-inferior glycemic control
compared to mealtime NovoLog®, both in combination withmetformin. In addition, mealtime FIASP® in a basal-bolus regimenwith metformin also provided statistically significant improvementin the overall glycemic control compared to basal insulin therapyalone with metformin in adult patients with type 2 diabetes.
14.2 Type 1 Diabetes - Adults
Study A (NCT01831765): FIASP® added to insulin detemir in patientswith Type 1 DM inadequately controlled at baseline.
The efficacy of FIASP® was eva luated in a 26-week, randomized,active controlled, treat-to-target, multicenter trial in 1143 adultpatients with type 1 diabetes inadequately controlled at baseline.
Patients were randomized to either blinded mealtime FIASP®(N=381), blinded mealtime NovoLog® (N=380), or open-labelpostmeal FIASP® (N=382), all in combination with once or twicedaily insulin detemir. At randomization, patients were switched toFIASP® on a unit to unit basis. Mealtime FIASP® or NovoLog® wasinjected 0-2 minutes before the meal, and postmeal FIASP® wasinjected 20 minutes after the start of the meal.
The mean age of the randomized subjects was 44.4 years and meanduration of diabetes was 19.9 years. 59% were male, 93% wereWhite, 2% were Black or African American, and 7% were Hispanic.
The mean BMI was 26.7 kg/m2.
After 26 weeks of treat |
