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PI & CMI Trade Names and Active Ingredients containing insulin glulisine. 1 Documents available. Need more information on a Apidra, CMIPI, Insulin glulisine. PI & CMI Trade Names and Active Ingredients containing insulin. 42 Documents Actrapid, PI, Insulin – human (human insulin) Apidra, CMIPI, Insulin glulisine. Apidra PI MKT. #v Page 1. PRODUCT INFORMATION. APIDRA APIDRA [insulin glulisine injection {rDNA origin}] is a recombinant human insulin .

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Management of children with type 1 diabetes has seen a shift in favor of mimicking normal physiological insulin responses with multiple daily injections or continuous subcutaneous insulin infusions CSII.

Few studies have compared the rapid-acting insulin analogs in this population but limited data indicate that glulisine is as effective as lispro when used in a basal—bolus regimen. This review appraises the current available studies and reviews on insulin glulisine in children.

These studies have suggested that glulisine is safe, well tolerated, and is an effective option in the diabetes armamentarium. Further studies are needed to determine apidrx safety for use in CSII pumps in the pediatric population. Type 1 diabetes mellitus is one of the most common chronic diseases in children in the developed world. In recent years, particularly because of improved insulins and insulin delivery devices, it has been possible apdra lower blood glucose levels apjdra easily with a reduced risk of hypoglycemia, thus decreasing the chances of microvascular, macrovascular, and neuropathic damage ie, diabetes complications in the future.

Metabolic memory is based on the concept that initial poor glycemic control during the diabetes disease course is associated with an increased risk of diabetes complications, despite optimal glycemic control later in the disease course and vice versa.

This emphasizes the desirability of attaining and maintaining excellent glycemic control from the time of diagnosis. However, in children and adolescents with type 1 diabetes, this may be difficult to obtain as a result of the need to balance multiple daily insulin injections with variations in dietary and exercise patterns. The approach to diabetes management is complex, and hypoglycemia arising from attempts to achieve normoglycemia or near-normoglycemia is understandably feared by children, parents, and clinicians.

Despite this, in recent years, there has been a shift in the approach to managing children with newly diagnosed type 1 diabetes, in order to optimize their glycemic control.

This has been aided by the availability and accepted use of insulin analogs, insulin pens, and continuous subcutaneous insulin infusions CSII pumps. Insulin analogs were first available for clinical use ina major advantage being reduced hypoglycemic episodes compared with regular human insulin RHI; Figure 1. The participants of these studies were aged 4 to 17 years of age of either sex. All participants had confirmatory type 1 diabetes. The main outcome data in the efficacy studies were changes in HbA 1c at study completion.

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To date, efficacy data on type 2 diabetes in the pediatric population have not been studied, but several trials have been performed in adults. Apjdra searching was made by cross referencing original articles and reviews.

Abstracts apkdra screened from major meetings and the abstract included in this review was sourced from Diabetologica. Enquiries were made to sanofi-aventis on future research, there are two ongoing Phase IV clinical trials currently in progress, the results of which are yet to be published.

These trials have not yet completed recruitment. This review will describe the pharmacokinetic and pharmacodynamic studies, available in children.

The efficacy trials will focus on comparison of glulisine with insulin lispro. The safety concerns and quality of life issues will be discussed based on the available trials in children.

The chemical name of insulin glulisine is 3B-LysBGlu-human insulin. Glulisine is the newest addition to the class of rapid-acting recombinant insulin analogs. Lispro is created by substituting proline for lysine at position B28 and lysine for proline at position B29, effectively reversing the amino acids sequence at positions 28 and 29 of the insulin beta-chain Figure 3.

Aspart is homologous to RHI except for the substitution of proline for aspartic acid at B28 Apudra 4. In solution, insulin molecules exist in equilibrium between monomers, dimers, tetramers, hexamers, and higher-order aggregates.

Human insulin is best absorbed in its monomeric form but, at physiologic pH, normal insulin molecules tend to associate into dimers and subsequently hexamers in the presence of zinc. Consequently, the absorption of RHI is limited by the degree and strength of self association of insulin molecules. The amino acid substitutions of glulisine and other rapid-acting insulin analogs promote monomer stability, allowing for rapid dissociation and absorption after subcutaneous injection.


In addition, the isolectric point pI is lowered to 5. The dimer and hexameric forms of human insulin confer conformational stability and are less likely to denature in storage. Unlike the other rapid-acting insulin analogs, the oligomeric molecules of glulisine are stable without the addition of zinc, presumably because of the unaltered proline at position B28 thus allowing dimerization.

Insulin and its analogs lower serum glucose levels by facilitating glucose uptake in skeletal muscle and fat, and by inhibiting gluconeogenesis, glycogenolysis, lipolysis, and proteolysis through its effect on the insulin receptor. Compared with RHI, there are no differences in association, dissociation, or receptor binding affinity. There have been limited studies in children evaluating pharmacokinetics and pharmacodynamics of glulisine. A double-blind, randomized, crossover study of 20 pediatric patients incorporated a single-dose 0.

Patients were stratified into two groups of 10 patients each: The trend persisted when children aipdra adolescents were analyzed separately see Table 3. Pharmacokinetics, prandial glucose control, and safety of insulin glulisine in children and adolescents with type 1 diabetes.

The role of insulin glulisine to improve glycemic control in children with diabetes mellitus

There are currently no pharmacokinetic studies comparing glulisine with lispro or aspart. An Ovid Medline search of the published literature found a limited number of articles on the use of glulisine among pediatric patients. There was one published pharmacokinetic study, 22 three review articles, 2324 and a recent abstract 25 detailing the safety and efficacy of lispro versus glulisine.

Although the data are limited, the literature is in favor of the general efficacy of glulisine as a rapid-acting analog in pediatric patients.

There are insufficient data to support its efficacy and safety via CSII. A week, multicenter, centrally randomized noninferiority trial compared the efficacy of glulisine with lispro in children aged 4 to 17 years with type 1 diabetes treated with basal insulin either glargine once daily or NPH twice daily.

However, the percentage of patients achieving American Diabetes Association ADA age-specific HbA 1c targets at endpoint was significantly higher with glulisine This difference was particularly pronounced in adolescents 13 to 17 years Based on these findings, Philotheou et al 25 concluded that glulisine is noninferior to lispro in the long-term reduction of HbA 1c in pediatric patients with type I diabetes. Several well designed trials have studied glulisine with and without basal insulin with comparator insulin analogs in adults.

In adults with type 1 diabetes the efficacy has been investigated in three randomized, active-controlled, noninferiority studies.

The baseline characteristics of these adult type 1 diabetes participants were similar between the two groups glulisine vs lispro. Glulisine in both studies was noninferior to lispro and the increase in basal insulin glargine dose in glulisine recipients was lower than in the lispro group. There were no trials comparing the efficacy of glulisine with aspart in pediatric patients. Glulisine has not been approved by the Food Drug Administration for use in children or adults via CSII, but two clinical 2627 and two in vitro studies have investigated its use.

One study, performed in adult patients, was a week multicenter, randomized trial that compared the efficacy and safety of glulisine versus aspart used in CSII in 59 patients with type I diabetes. Each treatment group showed a slight increase in mean HbA 1c over the 12 weeks 0. The second clinical study, which included adolescents and adults, was a crossover trial looking at timing of meal-related glulisine bolus administration via CSII in 23 subjects. An important property of insulin products in CSII is their ability to remain soluble and resist precipitation when exposed to various environments.

Although the longest duration clinical study using CSII with glulisine did not show any increase in catheter occlusion rates compared with aspart, 19 in vitro studies suggest glulisine could theoretically be more liable to precipitate. One study, utilizing reverse-phase high performance liquid chromatography to assess resistance to isoelectric precipitation of various types of insulin, 16 found that the resistance was highest for aspart and lowest for glulisine, but the clinical significance of this is unclear.

A second in vitro study assessed the stability of glulisine and aspart during simulated use in insulin pumps flow rates 0.

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Glulisine has also been shown to be more prone than aspart to form insoluble insulin fibrils, which are not biologically potent. On the basis of these studies, it is clear that further studies will be required before glulisine can be approved for use in CSII. There are two Phase IV ongoing trials with glulisine in children and adolescents with type 1 diabetes. To date no data are available see Table 4. Studies suggest that glulisine has a similar safety profile to the other new rapid-acting insulin analogs and that it is well tolerated.


The most common adverse event with glulisine, as with all insulins is hypoglycemia. Philotheou et al 25 conducted a week multicenter open centrally randomized, parallel group, noninferiority trial of children and adolescents, aged 4 to 17 years with pj 1 diabetes using glargine once daily in the evening or NPH twice daily as basal insulin and glulisine or lispro as the bolus apiera.

Despite a significantly higher percentage of patients on glulisine achieving ADA age-specific HbA 1c targets at endpoint A small crossover trial of 10 children and 10 adolescent patients with type 1 diabetes comparing RHI and glulisine found no severe hypoglycemic events.

There are no trials of glulisine use in CSII in a purely pediatric population, but in a study in 59 adults with type 1 diabetes comparing glulisine with aspart a similar frequency of hypoglycemia was found between the two groups. In children no generalized hypersensitivity reactions have been reported, although there are few studies in this population.

Qpidra glulisine was compared with aspart in CSII in 59 adult patients with type 1 diabetes the frequency of infusion-site reactions was apidr between the two groups. There is no evidence that glulisine or any of the other rapid-acting insulin analogs cause increased mitogenesis, potentially leading to cancer, compared with RHI.

There is a theoretical concern that they could increase the risk of tumor development due to altered binding characteristics to insulin and insulin-like growth factor IGF -1 receptors caused by the structural changes made to the native insulin molecule. However, preclinical studies suggest that structural changes in glulisine compared with RHI are not associated with any risk of tumorigenesis.

Activation of IRS-1 was 6- to fold lower with glulisine. Stimulation of DNA qpidra was comparable for glulisine and RHI in K6 myoblasts and there was no difference in proliferative activity between the two insulins at 12 months.

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In another study, glulisine demonstrated the same association, dissociation- and insulin-receptor affinity kinetics as RHI. When glulisine was compared with RHI in a small crossover trial in 10 adolescents and 10 children with type 1 diabetes, no safety concerns arose.

Other than urticaria in a patient on RHI, details of the adverse reactions were not provided. There were no severe hypoglycemic events or clinically relevant abnormalities on physical examinations or in pathology tests. Lipodystrophy and weight gain can each occur in adult subjects on long-term glulisine therapy.

Although there are theoretical concerns that glulisine could be associated with an increase in catheter occlusion in CSII, 1627 the one study comparing glulisine with aspart in pumps did not show a significant difference in catheter occlusion, and rates for both were low. In general, use of rapid-acting insulin analogs gives greater flexibility for the timing of injections, especially important for children and teenagers.

Insulin administration can be given immediately prior to or immediately after a meal, with the dose being adjusted according to carbohydrate intake, blood glucose level, and physical activity.

The potential to give glulisine immediately after a meal, once food intake is known, can be invaluable in young children in whom carbohydrate and other food intake can vary widely and be difficult to predict. There are no data relating to treatment satisfaction in patients on glulisine versus RHI. However, a number of studies, mainly in adults, have shown higher satisfaction in subjects on lispro or aspart compared with RHI. No specific studies have addressed quality of life QoL in patients on glulisine.

Several large trials have studied glulisine in adult patients with type 1 and type 2 diabetes, but data in the pediatric population are limited. Glulisine compares favorably with other rapid-acting insulin analogs in the treatment of children with type 1 diabetes, but there is no evidence that it has superior safety or efficacy.

However, it has been shown to be noninferior to lispro in terms of efficacy and safety as part of a basal-bolus regimen in pediatric patients with type 1 diabetes. The pharmacokinetic and pharmacodynamic properties of glulisine appear to be similar in pediatric and adult patients. Glulisine has a similar kinetic profile to lispro and has a more rapid onset and shorter duration of action than RHI.