Treatment of adults, adolescents and children aged 6 years and above with diabetes mellitus where treatment with insulin is required.

APIDRA 100U/ML Solution for injection in a vial: Roztwór do wstrzykiwań we wstrzykiwaczu 100 j.m./ml

Summary of the safety profile Hypoglycaemia, the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement. Tabulated list of adverse reactions The following adverse reactions from clinical investigations are listed below by system organ class and in order of decreasing incidence (very common: ≥1/10; common: ≥1/100 to <1/10;

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypoglycaemia.

APIDRA 100U/ML Solution for injection in a vial

Q: Contraindications?

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypoglycaemia.

Q: Warnings?

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Transferring a patient to another type or brand of insulin must be done under strict medical supervision. Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal,

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues, fast-acting, for injection, ATC code: A10AB06. Mechanism of action Insulin glulisine is a recombinant analogue of human insulin that is equipotent to regular human insulin.‍‍‍‍‍‍‍ Insulin glulisine has a more rapid onset of action and a shorter duration of action than regular human insulin. The primary activity of insulin and insulin analogues, including insulin glulisine, is regulation of glucose metabolism. Insulins lower blood glucose levels by stimulating peripheral glucose uptake, particularly by skeletal muscle and fat, and by inhibiting hepatic gluconeogenesis. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis and enhances protein synthesis. Studies in healthy volunteers and patients with diabetes showed that insulin glulisine, when given subcutaneously, has a more rapid onset and shorter duration of action than regular human insulin. When insulin glulisine is administered by subcutaneous injection, the blood glucose-lowering effect begins within 10–20 minutes. After intravenous administration, a more rapid onset and shorter duration of action, as well as a greater peak effect, were observed compared with subcutaneous administration. The blood glucose-lowering effects of insulin glulisine and regular human insulin are equipotent when administered intravenously. One unit of insulin glulisine has the same blood glucose-lowering activity as one unit of regular human insulin. Dose proportionality In a study involving 18 male subjects with type 1 diabetes mellitus aged 21 to 50 years, insulin glulisine displayed dose-proportional blood glucose-lowering effects in the therapeutically relevant dose range of 0.075 to 0.15 units/kg. At doses of 0.3 units/kg or higher, the blood glucose-lowering effect of insulin glulisine was less than dose-proportional, similar to regular human insulin. The onset of action of insulin glulisine is twice as rapid as that of regular human insulin, and its blood glucose-lowering effect ends approximately 2 hours earlier than that of regular human insulin. A Phase I study in patients with type 1 diabetes mellitus evaluated the blood glucose-lowering profiles of insulin glulisine and regular human insulin administered subcutaneously at a dose of 0.15 units/kg at different times relative to a 15-minute standard meal. Data showed that insulin glulisine given 2 minutes before a meal provided similar postprandial glycaemic control compared with regular human insulin given 30 minutes before a meal. When given 2 minutes before a meal, insulin glulisine provided better postprandial glycaemic control than regular human insulin given 2 minutes before a meal. Insulin glulisine given 15 minutes after the start of a meal provided similar glycaemic control to regular human insulin given 2 minutes before a meal (see Figure 1). Figure 1A Figure 1B Figure 1C Figure 1: Mean blood glucose-lowering effect over 6 hours in 20 patients with type 1 diabetes mellitus. Insulin glulisine given 2 minutes (Glulisine pre) before the start of a meal compared with regular human insulin given 30 minutes (Regular human insulin −30 min) before the start of a meal (Figure 1A) and compared with regular human insulin given 2 minutes (Regular human insulin pre) before a meal (Figure 1B). Insulin glulisine given 15 minutes (Glulisine post) after the start of a meal compared with regular human insulin given 2 minutes (Regular human insulin pre) before the start of a meal (Figure 1C). On the x-axis, zero (arrow) is the start of a 15-minute meal. Obesity A Phase I study conducted with insulin glulisine, insulin lispro and regular human insulin in an obese population demonstrated that insulin glulisine maintained its rapid-acting properties. In this study, the time to early blood glucose-lowering activity representing 20% of total AUC and the AUC(0–2 h) were 114 minutes and 427 mg/kg respectively for insulin glulisine, 121 minutes and 354 mg/kg for lispro, and 150 minutes and 197 mg/kg for regular human insulin (see Figure 2). Figure 2: Glucose infusion rate (GIR) following subcutaneous injection of 0.3 units/kg of insulin glulisine (GLULISINE) or insulin lispro (LISPRO) or regular human insulin (Regular human insulin) in an obese population. Another Phase I study with insulin glulisine and insulin lispro in a non-diabetic population of 80 subjects with a wide range of body mass indices (18–46 kg/m²) demonstrated that rapid onset of action was generally maintained across a wide range of body mass indices (BMI), while total blood glucose-lowering effect decreased with increasing obesity. The mean total GIR AUC between 0–1 hour was 102±75 mg/kg with 0.2 units/kg of insulin glulisine and 158±100 mg/kg with 0.4 units/kg of insulin glulisine, and 83.1±72.8 mg/kg with 0.2 units/kg of insulin lispro and 112.3±70.8 mg/kg with 0.4 units/kg of insulin lispro. A Phase I study in 18 obese patients with type 2 diabetes mellitus (BMI between 35 and 40 kg/m²) with insulin glulisine and insulin lispro [90% CI: 0.81, 0.95 (p=<0.01)] demonstrated that insulin glulisine effectively controls diurnal postprandial blood glucose excursions. Clinical efficacy and safety Type 1 diabetes mellitus – Adults In a 26-week Phase III clinical study comparing insulin glulisine with insulin lispro both administered subcutaneously shortly (0–15 minutes) before a meal in patients with type 1 diabetes mellitus using insulin glargine as basal insulin, insulin glulisine was comparable to insulin lispro in terms of glycaemic control as demonstrated by changes in glycated haemoglobin from baseline to endpoint (expressed as HbA1c equivalent). Comparable self-monitored blood glucose values were observed. Unlike insulin lispro, treatment with insulin glulisine did not require an increase in the basal insulin dose. A 12-week Phase III clinical study conducted in patients with type 1 diabetes mellitus receiving insulin glargine as basal therapy showed that administration of insulin glulisine immediately after a meal provided comparable efficacy to insulin glulisine administered immediately (0–15 minutes) before a meal or to regular human insulin administered 30–45 minutes before a meal. In the per-protocol population, the glulisine pre-meal group showed a significantly greater reduction in glycated haemoglobin compared with the regular human insulin group. Type 1 diabetes mellitus – Paediatric population A 26-week Phase III clinical study compared subcutaneous administration of insulin glulisine with insulin lispro given shortly (0–15 minutes) before a meal in children (4–5 years: n = 9; 6–7 years: n = 32; and 8–11 years: n = 149) and adolescents (12–17 years: n = 382) with type 1 diabetes mellitus who received insulin glargine or NPH insulin as basal insulin. Insulin glulisine achieved comparable glycaemic control as assessed by the change in glycated haemoglobin (GHb expressed as HbA1c equivalent) from baseline to endpoint and by self-monitored blood glucose values compared with insulin lispro. There is insufficient clinical information on the use of Apidra in children under the age of 6 years. Type 2 diabetes mellitus – Adults A 26-week Phase III clinical study followed by a 26-week safety extension study was conducted to compare insulin glulisine (0–15 minutes before a meal) with regular human insulin (30–45 minutes before a meal) administered subcutaneously in patients with type 2 diabetes mellitus also using NPH insulin as basal insulin. The mean body mass index (BMI) of patients was 34.55 kg/m². Insulin glulisine was shown to be comparable with regular human insulin with regard to changes in glycated haemoglobin (expressed as HbA1c equivalent) from baseline to 6-month endpoint (−0.46% for insulin glulisine and −0.30% for regular human insulin) and from baseline to 12-month endpoint (−0.23% for insulin glulisine and −0.13% for regular human insulin; the difference was not significant). In this study, the majority of patients (79%) mixed their rapid-acting insulin with NPH insulin immediately before injection, and 58% of patients were using oral antidiabetic agents at the time of randomisation. These patients were instructed to continue taking them at the same doses. Race and gender In controlled clinical studies in adults, insulin glulisine showed no differences in safety and efficacy in subgroup analyses based on race and gender.

⚠️ Warnings

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Transferring a patient to another type or brand of insulin must be done under strict medical supervision.‍‍‍‍‍‍‍ Changes in strength, brand (manufacturer), type (regular, NPH, lente, long-acting, etc.), origin (animal, human, human insulin analogue) and/or method of manufacture may result in the need for a change in dose. Concomitant oral antidiabetic treatment may need to be adjusted. Patients must be instructed to continuously rotate the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hyperglycaemia Administration of inadequate doses or discontinuation of treatment, particularly in insulin-dependent diabetic patients, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal. Hypoglycaemia The time of occurrence of hypoglycaemia depends on the action profile of the insulins used and may therefore change when the treatment regimen is changed. Conditions in which the early warning symptoms of hypoglycaemia may be altered or be less pronounced include long duration of diabetes, intensification of insulin therapy, diabetic neuropathy, medicinal products such as beta-blockers or transfer from animal to human insulin. Dose adjustment may be necessary in patients who increase their physical activity or change their usual meal plan. Exercise taken immediately after a meal may increase the risk of hypoglycaemia. Compared with regular human insulin, if hypoglycaemia occurs after injection of a rapid-acting insulin analogue, it may occur sooner. Uncorrected hypoglycaemic or hyperglycaemic reactions may cause unconsciousness, coma or death. Insulin requirements may be altered during illness or emotional disturbance. Apidra 100 units/ml solution for injection in a cartridge Pens to be used with Apidra 100 units/ml solution for injection in a cartridge: Apidra 100 units/ml in cartridges is suitable only for subcutaneous injections administered with a reusable pen. If administration by syringe, intravenous injection or infusion pump is necessary, a vial should be used. Apidra cartridges may only be used with the following pens: JuniorSTAR, which delivers Apidra in 0.5-unit dose increments ClikSTAR, Tactipen, Autopen 24, Allstar and AllStar PRO, which deliver Apidra in 1-unit dose increments. These cartridges must not be used with any other reusable pens, as dosing accuracy has been established only with the listed pens (see sections 4.2 and 6.6). Not all of these pens may be marketed in your country. Medication errors Medication errors have been reported in which other insulins, particularly long-acting insulins, have been accidentally administered instead of insulin glulisine. The insulin label must always be checked before each injection to avoid mix-ups between insulin glulisine and other insulins. Apidra 100 units/ml solution for injection in a vial Continuous subcutaneous insulin infusion Insulin pump or infusion set malfunction or handling errors may rapidly lead to hyperglycaemia, ketosis and diabetic ketoacidosis. Prompt identification and correction of the cause of hyperglycaemia or ketosis or diabetic ketoacidosis is necessary. Cases of diabetic ketoacidosis have been reported when Apidra was administered by a subcutaneous insulin infusion pump system. Most of these cases were associated with handling errors or pump system failures. Interim subcutaneous injection of Apidra may be required. Patients receiving Apidra by continuous subcutaneous infusion pump must be trained in the administration of insulin by injection and must have an alternative insulin delivery system available in case of pump failure (see sections 4.2 and 4.8). Excipients This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. it is essentially sodium-free. Apidra contains metacresol, which may cause allergic reactions. Combination of Apidra with pioglitazone Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac failure. This should be kept in mind if treatment with the combination of Apidra and pioglitazone is considered. If this combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Apidra SoloStar 100 units/ml solution for injection in a pre-filled pen Handling of SoloStar pre-filled pen Apidra SoloStar 100 units/ml in a pre-filled pen is suitable only for subcutaneous injections. If administration by syringe, intravenous injection or infusion pump is necessary, a vial should be used. Before using SoloStar, the instructions for use included in the package leaflet must be read carefully. SoloStar must be used as recommended in these instructions for use (see section 6.6).

APIDRA 100U/ML Solution for injection in a vial

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