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

APIDRA 100U/ML Solution for injection in a vial: Roztwór do wstrzykiwań we wkładzie 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 relative to the insulin requirement. Tabulated list of adverse reactions The following adverse reactions observed during clinical trials 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 carried out under strict medical supervision. Changes in strength, brand (manufacturer), type (regular soluble, neutral protamine Hagedorn [NPH],

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 action of insulin and insulin analogues, including insulin glulisine, is the 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 have shown 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 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 glucose-lowering effects of insulin glulisine and regular human insulin are equipotent when administered intravenously. One unit of insulin glulisine has the same glucose-lowering effect 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 lowered blood glucose levels proportionally to the administered dose within the therapeutically relevant dose range of 0.075 to 0.15 units/kg. At doses of 0.3 units/kg or higher, the hypoglycaemic effect of insulin glulisine was less than dose-proportional, similarly to human insulin. The onset of action of insulin glulisine is twice as fast as that of regular human insulin, and its hypoglycaemic 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 glucose-lowering profiles of insulin glulisine and regular soluble insulin administered subcutaneously at a dose of 0.15 units/kg at various times relative to a 15-minute standard meal. Data showed that insulin glulisine given 2 minutes before a meal provided postprandial glycaemic control comparable to that of regular soluble human insulin given 30 minutes before a meal. When given 2 minutes before a meal, insulin glulisine provided better postprandial glycaemic control than regular soluble human insulin given 2 minutes before a meal. Insulin glulisine given 15 minutes after the start of a meal provided glycaemic control comparable to that of regular soluble human insulin given 2 minutes before a meal (see Figure 1). Figure 1A Figure 1B Figure 1C Figure 1: Mean 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 soluble insulin -30 min) before the start of a meal (Figure 1A) and compared with regular human insulin given 2 minutes (Regular soluble insulin pre) before a meal (Figure 1B). Insulin glulisine given 15 minutes (Glulisine post) after the start of a meal compared with regular insulin given 2 minutes (Regular soluble insulin pre) before the start of a meal (Figure 1C). On the x-axis, zero (arrow) is the start of the 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 maintains its rapid-acting properties. In this study, the time representing early glucose-lowering activity up to 20% of total AUC and 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) after subcutaneous injection of 0.3 units/kg of insulin glulisine (GLULISINE) or insulin lispro (LISPRO) or regular human insulin (Regular soluble 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 the rapid onset of action was maintained across a wide range of body mass indices (BMI), while the overall hypoglycaemic effect decreased with increasing obesity. The mean total GIR AUC (glucose infusion rate – area under the curve) 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 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 basal insulin dose. A 12-week phase III clinical study conducted in patients with type 1 diabetes mellitus receiving insulin glargine as basal therapy indicates that administration of insulin glulisine immediately after a meal provides efficacy comparable to that of insulin glulisine given immediately (0–15 minutes) before a meal or regular soluble insulin given 30–45 minutes before a meal. In the per-protocol population, a significantly greater reduction in glycated haemoglobin was observed in the pre-meal glulisine group compared with the regular soluble 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 were receiving 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 study end and by self-monitored blood glucose values, compared with insulin lispro. Insufficient clinical data are available on the use of Apidra in children below 6 years of age. 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 soluble human insulin (30–45 minutes before a meal) administered subcutaneously in patients with type 2 diabetes mellitus using NPH insulin as basal insulin. Mean body mass index (BMI) of patients was 34.55 kg/m². Insulin glulisine was shown to be comparable to regular soluble human insulin with regard to changes in glycated haemoglobin (expressed as HbA1c equivalent) from baseline to end of the 6-month study (−0.46% for insulin glulisine and −0.30% for regular soluble human insulin) and from baseline to end of the 12-month study (−0.23% for insulin glulisine and −0.13% for regular soluble human insulin; difference 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 carried out under strict medical supervision.‍‍‍‍‍‍‍ Changes in strength, brand (manufacturer), type (regular soluble, neutral protamine Hagedorn [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 dosage. Concomitant oral antidiabetic treatment may need to be adjusted. Patients must be instructed to continuously rotate injection sites to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following injection into 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 a change in injection site, and dose adjustment of antidiabetic medicinal products 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 fatal. 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 early warning symptoms may be altered or less pronounced include long duration of diabetes, intensification of insulin therapy, diabetic neuropathy, medicinal products such as beta-blockers, or transfer from animal-source insulin to human insulin. Dose adjustment may be necessary in patients who increase their physical activity or change their usual meal plan. Exercise performed immediately after a meal may increase the risk of hypoglycaemia. Compared with regular soluble human insulin, if hypoglycaemia occurs after injection of a rapid-acting insulin analogue, it may occur earlier. Uncontrolled 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 cartridges: 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 increments ClikSTAR, Tactipen, Autopen 24, Allstar, and AllStar PRO, which deliver Apidra in 1-unit increments. These cartridges must not be used with any other reusable pens, as dosing accuracy has been established only with the above-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 via a continuous subcutaneous insulin infusion pump system. The majority of these cases were related to handling errors or pump system failures. Interim subcutaneous insulin injection may be necessary. Patients treated with continuous subcutaneous insulin infusion pumps must be trained in insulin injection technique 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 the 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 cardiac 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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