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Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, fast-acting. ATC code: A10AB05.
Pharmacology: Pharmacodynamics: Mechanism of Action: SANSULIN Rapid produces a more rapid onset of action compared to soluble human insulin, together with a lower glucose concentration, as assessed within the first four hours after a meal. SANSULIN Rapid has a shorter duration of action compared to soluble human insulin after subcutaneous injection.
When SANSULIN Rapid is injected subcutaneously, the onset of action will occur within 10 to 20 minutes of injection. The maximum effect is exerted between 1 and 3 hours after injection. The duration of action is 3 to 5 hours.
Insulin aspart is equipotent to soluble human insulin on a molar basis.
Adults: Clinical trial reports in patients with type 1 diabetes have demonstrated a lower postprandial blood glucose with innovator product compared to soluble human insulin. In two long-term open label trials in patients with type 1 diabetes comprising 1,070 and 884 patients, respectively, insulin aspart reduced glycated haemoglobin by 0.12 percentage points and by 0.15 percentage points compared to soluble human insulin; a difference of limited clinical significance.
Clinical trials in patients with type 1 diabetes have demonstrated a reduced risk of nocturnal hypoglycaemia with insulin aspart compared to soluble human insulin. The risk of daytime hypoglycaemia was not significantly increased.
Elderly: In a reported PK/PD trial, the relative differences in the PD properties between insulin aspart and soluble human insulin in the elderly patients with type 2 diabetes were similar to those seen in healthy subjects and younger patients with diabetes.
Children and adolescents: When given to children, insulin aspart showed similar long-term glucose control compared to soluble human insulin. In reported clinical trials for children and adolescents aged 2 to 17 the pharmacodynamics profile of insulin aspart in children was similar to that seen in adults.
Pregnancy: A clinical trial report comparing safety and efficacy of insulin aspart vs. soluble human insulin in the treatment of pregnant women with type 1 diabetes (322 exposed pregnancies) did not indicate any adverse effect of insulin aspart on pregnancy or on the health of the foetus/newborn.
In addition, the data from a clinical trial reported from innovator, including 27 women with gestational diabetes randomised to treatment with insulin aspart vs. soluble human insulin showed similar safety profiles between treatments as well as a significant improvement in postprandial glucose control in the insulin aspart treated group.
Pharmacokinetics: In reported data of innovator product substitution of amino acid proline with aspartic acid as position B28 reduces the tendency to form hexamers as observed with soluble human insulin. Insulin aspart is therefore more rapidly absorbed from the subcutaneous layer compared to soluble human insulin.
The time to maximum concentration is, on average, half of that for soluble human insulin. A mean maximum plasma concentration of 492 pmol/l was reached 40 minutes after a subcutaneous dose of 0.15 U/kg bodyweight in type 1 diabetic patients. The insulin concentrations returned to baseline about 4 to 6 hours after dose. The absorption rate was somewhat slower in type 2 diabetic patients, resulting in a lower Cmax (352 ± 240 pmol/l) and later tmax (60 minutes). The intra-individual variability in time to maximum concentration is significantly less for insulin aspart product than for soluble human insulin, whereas the intra-individual variability in Cmax for insulin aspart product is larger.
Children and adolescents: The pharmacokinetic and pharmacodynamic properties of insulin aspart product were investigated in children and adolescents with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, Cmax differed between the age groups, stressing the importance of the individual titration of insulin aspart.
Elderly: The relative differences in pharmacokinetic properties between insulin aspart and soluble human insulin in elderly patients with type 2 diabetes were similar to those observed in healthy subjects and in younger patients with diabetes. A decreased absorption rate was observed in elderly patients, resulting in a later tmax (82 minutes), whereas Cmax was similar to that observed in younger patients with type 2 diabetes and slightly lower than in patients with type 1 diabetes.
Hepatic impairment: In patients with hepatic impairment tmax was delayed to about 85 min. (50 min. in subjects with normal hepatic function) while AUC, Cmax and CL/F were similar.
Renal impairment: A single dose pharmacokinetic reported study of insulin aspart in 18 subjects with normal to severely impaired renal function was performed. No apparent effect of creatinine clearance values on AUC, Cmax, CL/F and tmax of insulin aspart was found. Data were limited in patients with moderate and severe renal impairment. Patients with renal failure necessitating dialysis treatment were not investigated.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction. In in vitro tests, including binding to insulin and IGF-1 receptor sites and effects on cell growth, insulin aspart behaved in a manner that closely resembled human insulin. Studies also demonstrate that the dissociation of binding to the insulin receptor of insulin aspart is equivalent to human insulin.
Non-clinical data reveal no observable adverse reaction level of the insulin aspart injection on conventional studies of toxicity, toxicokinetic characteristic and immunogenicity test.
Clinical Study: A 24-week-long clinical study compared biosimilar product (insulin aspart injection fluid) to innovator product in patients with type 1 or type 2 diabetes using parameters of HbA1c, fasting blood glucose, and 2-hr post-meal blood glucose, which is venous blood glucose levels as determination criteria.
After 24 weeks of treatment, the biosimilar group and innovator group achieved an HbA1c target of < 7.0%, that were 52.61% and 51.01% for each group. The percentage difference between the two groups was 1.6%. The percentages of the two groups that achieved an HbA1c target of ≤ 6.5% were 34.24% and 30.87%, for a difference of 3.37%. The data were no statistically significant difference: Statistical results of the decrease in HbA1c until the 24th week.
The decrease in HbA1c until 24th week was -2.20 (biosimilar group) vs -2.32 (innovator group) for fasting state and -2.38 (biosimilar group) vs -2.40 (innovator group) for 2 hours after the start of a meal with p-value < 0.0001. The 95% confidence interval between the biosimilar group and innovator group was 0.04 (-0.17; 0.26) of fasting state and -0.10 (-0.29; 0.09) of 2 hours after the start of a meal.
Statistical results of change in fasting blood glucose levels between baseline and the 24th week.
Change in fasting blood glucose levels between baseline and the 24th week with a mean of -2.02 (biosimilar group) vs -1.70 (innovator group) in the fasting state and -2.21 (biosimilar group) vs -1.77 (innovator group) for 2 hours after the start of a meal with p-value < 0.001.
Statistical results of changes in blood glucose levels for 2 hours after the start of a meal between baseline and the 24th week.
Change in blood glucose levels for 2 hours after the start of a meal between baseline and the 24th week with a mean value of -6.14 (biosimilar group) vs -6.29 (innovator group) in the fasting state and -6.62 (biosimilar group) vs -6.48 (innovator group) for 2 hours after the start of a meal, with p-value < 0.001.
Aside from hypoglycemic events, the adverse reactions reported by the two groups were similar. The researchers determined that all trial drug-associated adverse reaction were less than 5%.
