Pharmacotherapeutic Group: Antidiabetic agent. Insulins and analogues for injection, intermediate-acting combined with fast-acting. ATC Code: A10AD05.
Pharmacology: Pharmacodynamics: Novomix 30 is a biphasic suspension of insulin aspart (rapid-acting human insulin analogue) and protamine-crystallised insulin aspart (intermediate-acting human insulin analogue).
The blood glucose-lowering effect of insulin occurs when the molecules facilitate the uptake of glucose by binding to insulin receptors on muscle and fat cells, and simultaneously inhibit the output of glucose from the liver.
NovoMix 30 is a biphasic insulin which contains 30% soluble insulin aspart. This has a rapid onset of action, thus allowing it to be given closer to a meal (within 0-10 min of the meal) when compared to soluble human insulin. The crystalline phase (70%) consists of protamine-crystallised insulin aspart which has an activity profile that is similar to that of human neutral protamine hagedorn (NPH) insulin.
When NovoMix 30 is injected SC, the onset of action will occur within 10-20 min of injection. The maximum effect is exerted between 1 and 4 hrs after injection. The duration of action is up to 24 hrs.
In a 3-month trial in patients with types 1 and 2 diabetes, NovoMix 30 showed equal control of glycosylated haemoglobin compared to treatment with biphasic human insulin 30. Insulin aspart is equipotent to human insulin on a molar basis.
In 1 study, 341 patients with type 2 diabetes were randomised to treatment with NovoMix 30 either alone or in combination with metformin or to metformin together with sulfonylurea. The primary efficacy variable glycosylated haemoglobin (HbA1C) after 16 weeks of treatment did not differ between patients with Novomix 30 combined with metformin and patients with metformin plus sulfonylurea. In this trial, 57% of the patients had baseline HbA1C above 9%; in these patients treatment with NovoMix 30 in combination with metformin resulted in significantly lower HbA1C than metformin in combination with sulfonylurea.
In 1 study, patients with type 2 diabetes, insufficiently controlled on oral hypoglycaemic agents alone, were randomised to treatment with NovoMix 30 twice daily (117 patients) or insulin glargine once daily (116 patients). After 28 weeks treatment following the dosing guideline, the mean reduction in HbA1C was 2.8% with NovoMix 30 (mean at baseline=9.7%). With NovoMix 30, 66% and 42% of the patients reached HbA1C levels <7% and 6.5%, respectively, and the mean FPG was reduced about 7 mmol/L (from 14 mmol/L at baseline to 7.1 mmol/L).
Children and Adolescents: A 16-week clinical trial comparing postprandial glycaemic control of meal-related NovoMix 30 with meal-related human insulin/biphasic human insulin 30 and bedtime NPH insulin was performed in 167 subjects 10-18 years. Mean HbA1C remained similar to baseline throughout the trial in both treatment groups, and there was no difference in hypoglycaemia rate with NovoMix 30 or biphasic human insulin 30.
In a smaller (54 subjects) and younger (6-12 years) population, treated in a double-blind, cross-over trial (12 weeks on each treatment) the rate of hypoglycaemic episodes and the postprandial glucose increase was significantly lower with NovoMix 30 compared to biphasic human insulin 30. Final HbA1C was significantly lower in the biphasic human insulin 30-treated group compared with NovoMix 30.
Pharmacokinetics: In insulin aspart, substitution of amino acid proline with aspartic acid at position B28 reduces the tendency to form hexamers in the soluble fraction of NovoMix 30, as compared with soluble human insulin. The insulin aspart in the soluble phase of NovoMix 30 comprises 30% of the total insulin; this is absorbed more rapidly from the subcutaneous layer than the soluble insulin component of biphasic human insulin. The remaining 70% is in crystalline form as protamine-crystallised insulin aspart; this has a prolonged absorption profile similar to human NPH insulin.
The maximum serum insulin concentration is, on average, 50% higher with NovoMix 30 than with biphasic human insulin 30. The time to maximum concentration is, on average, ½ of that for biphasic human insulin 30. In healthy volunteers, a mean maximum serum concentration of 140±32 pmol/L was reached about 60 min after SC dose of 0.2 units/kg body weight. The mean t½ of NovoMix 30, reflecting the absorption rate of the protamine bound fraction, was about 8-9 hrs. Serum insulin levels returned to baseline 15-18 hrs after SC dose. In type 2 diabetic patients, the maximum concentration was reached about 95 min after dosing, and concentrations well >0 for not less than 14 hrs post-dosing were measured.
Children and Adolescents: The pharmacokinetics of NovoMix 30 has not been investigated in children or adolescents. However, the pharmacokinetic and pharmacodynamic properties of soluble insulin aspart have been investigated in children 6-12 years and adolescents 13-17 years with type 1 diabetes. Insulin aspart was rapidly absorbed in both age groups, with similar tmax as in adults. However, peak plasma concentration (Cmax) differed between the age groups, stressing the importance of the individual titration of insulin aspart.
The pharmacokinetics of NovoMix 30 has not been investigated in elderly or patients with impaired renal or liver function.
Toxicology: Preclinical Safety Data: Nonclinical data with insulin aspart reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and 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.