Pharmacotherapeutic Group: Insunova-R: Insulins and analogues for injection, fast-acting, insulin (human). ATC Code: A10AB01.
Insunova-N: Insulins and analogues for injection, intermediate-acting, insulin (human). ATC Code: A10AC01.
Insunova-30/70: Insulins and analogues for injection, intermediate-acting combined with fast-acting, insulin (human). ATC Code: A10AD01.
Insunova-G: Drugs used in diabetes. Insulins and analogues for injection, long-acting.
Pharmacodynamics: Insulin, a hormone secreted by the β-cells of the pancreas, plays an essential role in controlling the metabolism and storage of carbohydrates, fat and protein. Insulin is secreted in response to a rise in blood glucose (sugar).
Mechanism of Action: The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and suppression of glucose output from the liver. Insulin in the blood stream has a half-life of a few minutes. Consequently, the time-action profile of an insulin preparation is determined solely by its absorption characteristics. This process is influenced by several factors (eg, insulin dosage, injection route and site), which is why considerable intra- and interpatient variability is seen.
Insunova-G: Insulin glargine is a human insulin analogue designed to have low solubility at a neutral pH. It is completely soluble at the acidic pH of the injection solution (pH 4). After injection into SC tissue, the acidic solution is neutralised leading to formation of microprecipitates from which small amounts of insulin glargine are continuously released, providing a smooth, peakless, predictable concentration/time profile with a prolonged duration of action.
Insulin Receptor Binding: Insulin glargine is very similar to human insulin with respect to insulin receptor binding kinetics and can therefore, be considered to mediate a similar effect via the insulin receptor.
The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogues lower blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat and by inhibiting hepatic glucose production. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis and enhances protein synthesis.
In clinical pharmacology studies, IV insulin glargine and human insulin have shown to be equipotent when given at the same doses. As with all insulins, the time course of action of insulin glargine may be affected by physical activity and other variables.
In euglycaemic clamp studies in healthy subjects or in patients with type 1 diabetes, the onset of action of SC insulin glargine was slower than neutral protamine hagedorn (NPH) human insulin. The efficacy profile of insulin glargine was relatively constant with no pronounced peak and the duration of its effect was prolonged compared to NPH human insulin.
The longer duration of action (up to 24 hrs) of insulin glargine is directly related to its slower rate of absorption and supports once daily SC administration. The time course of action of insulins, including insulin glargine, may vary between individuals and/or within the same individual.
In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar on administration of IV insulin glargine and human insulin both in healthy volunteers and in patients with type 1 diabetes.
In an another 5-year NPH-controlled study (NPH given twice daily) in 1024 type 2 diabetic patients, progression of retinopathy by ≥3 steps on the early treatment diabetic retinopathy study (ETDRS) scale was investigated by fundus photography. No significant difference was seen in the progression of diabetic retinopathy when insulin glargine was compared to NPH insulin.
Paediatric Population: In a randomised, controlled clinical study, paediatric patients (range 6-15 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. Insulin glargine was administered once daily at bedtime and NPH human insulin was administered once or twice daily. Similar effects on glycohaemoglobin and the incidence of symptomatic hypoglycaemia were observed in both treatment groups, however fasting plasma glucose decreased more from baseline in the insulin glargine group than in the NPH group. There was less severe hypoglycaemia in the insulin glargine group as well. One hundred and forty-three (143) patients treated with insulin glargine in this study continued treatment with insulin glargine in an uncontrolled extension study with mean duration of follow up of 2 years. No new safety signals were seen during this extended treatment with insulin glargine.
Clinical Studies: Efficacy of Biocon's insulin glargine was assessed in a phase 3 study conducted by Biocon limited to establish safety and non-inferiority (in comparison to reference product), with respect to decrease in glycosylated haemoglobin (HbA1c) in patients with type 1 diabetes mellitus.
The results established non-inferiority of Biocon's insulin glargine compared to the reference product, with respect to change in HbA1c. The changes in fasting plasma glucose (FPG), polypropylene glycol (PPG) and 7-point glucose were comparable between the 2 study arms. The proportion of patients who achieved target HbA1c <7% was comparable between groups. Mean insulin dose was also comparable between the 2 arms. Compliance was good during the study, with average compliance >98% for both basal and pre-meal soluble insulin which was comparable for both study arms.
Overall the 2 study treatments were comparable with respect to efficacy.
Pharmacokinetics: Insulin is metabolized in the liver and kidney; small amounts are metabolized in muscle and fat. It binds to cell surface receptors, is taken into the cells and is then degraded by glutathione insulin transhydrogenase to the A and B chains and by specific intracellular proteases. When injected subcutaneously, the onset of action will occur within 30 min of injection for both Insunova-R and Insunova 30/70, and within 1-1.5 hrs for Insunova-N (NPH).
The maximum peak effect is attained between 2 and 4 hrs for Insunova-R, between 2 and 8 hrs for Insunova-30/70, and within 4-8 hrs for Insunova-N (NPH).
The duration of action is 4-6 hrs for Insunova-R, and up to 24 hrs for both Insunova-30/70 and Insunova-N (NPH).
Insunova-G: In healthy subjects and in diabetic patients, insulin serum concentrations indicated a slower and much more prolonged absorption and showed a lack of a peak after subcutaneous injection of insulin glargine in comparison to human NPH insulin, concentrations were thus, consistent with the time profile of the pharmacodynamic activity of insulin glargine. Insulin glargine injected once daily will reach steady-state levels in 2-4 days after the 1st dose. When given IV the elimination half-life (t½) of insulin glargine and human insulin were comparable.
In man, insulin glargine is partly degraded in the SC tissue at the carboxyl terminus of the chain with formation of the active metabolites 21 A-Gly-insulin and 21 A-Gly-des-308-Thr-insulin.
Unchanged insulin glargine and degradation products are also present in plasma. In clinical studies, subgroup analyses based on age and gender did not indicate any difference in safety and efficacy in insulin glargine-treated patients compared to the entire study population.
Paediatric Population: No specific pharmacokinetics study in children or adolescents was conducted.
Toxicology: Preclinical Safety Data: The nonclinical studies performed with the human recombinant insulin reveals no special hazard to humans. Human insulin was not mutagenic in a series of in vitro and in vivo genotoxicity assays.
Insunova-G: Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.