Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.

ABASAGLAR 100U/ML Solution for injection in pre-filled pen: Roztwór do wstrzykiwań we wstrzykiwaczu 700 j/ml

Summary of the safety profile Hypoglycaemia (very common), generally the most frequent adverse reaction of insulin therapy, may occur if the insulin dose is too high in relation to the insulin requirement (see section 4.4). Tabulated list of adverse reactions The following related adverse reactions recorded in clinical studies are listed below by system organ class and in order of decreasing incid

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

ABASAGLAR 100U/ML Solution for injection in pre-filled pen

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ABASAGLAR 100U/ML Solution for injection in pre-filled pen — Description, Dosage, Side Effects | PillsCard

Pharmacotherapeutic group: Drugs used in diabetes, insulins and analogues for injection, long-acting, ATC code: A10AE04. ABASAGLAR is a so-called biosimilar medicine.‍‍‍‍‍‍‍ Detailed information is available on the European Medicines Agency website https://www.ema.europa.eu. Mechanism of action Insulin glargine is a human insulin analogue designed to have low solubility at neutral pH. It is completely soluble at the acidic pH (pH 4) of the ABASAGLAR injection solution. After injection into the subcutaneous tissue, the acidic solution is neutralised, leading to formation of microprecipitates from which small amounts of insulin glargine are continuously released, providing a smooth and predictable concentration/time profile with no peak and a prolonged duration of action. Insulin glargine is metabolised to 2 active metabolites, M1 and M2 (see section 5.2). Insulin receptor binding In vitro studies indicate that the affinity of insulin glargine and its metabolites M1 and M2 for the human insulin receptor is similar to that of human insulin. IGF-1 receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately 5 to 8 times greater than that of human insulin (but approximately 70 to 80 times lower than the affinity of IGF-1), while metabolites M1 and M2 bind to the IGF-1 receptor with slightly lower affinity compared with human insulin. The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than the concentration required for half-maximal occupancy of the IGF-1 receptor and subsequent activation of the mitogenic-proliferative pathway triggered by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found with insulin therapy, including ABASAGLAR therapy, are considerably lower than the pharmacological concentrations needed to activate the IGF-1 pathway. Pharmacodynamic effects 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 gluconeogenesis. Insulin inhibits lipolysis in adipocytes, inhibits proteolysis and enhances protein synthesis. In clinical pharmacology studies, intravenous insulin glargine and human insulin were 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 volunteers or in patients with type 1 diabetes mellitus, the onset of action of subcutaneously injected insulin glargine was slower than that of human NPH insulin. The effect profile of insulin glargine was smooth, without peaks, and with a prolonged duration of action. The following graph shows the results from a study in patients: Glucose utilisation Rate* (mg/kg/min) Fig. 1: Activity profile in type 1 diabetic patients insulin glargine ……… NPH insulin Time (h) after s.c. injection End of observation period *Determined as the amount of glucose infused to maintain constant plasma glucose levels (hourly mean values) The prolonged duration of action of subcutaneous insulin glargine is directly related to its slower rate of absorption and supports once-daily dosing. The time course of action of insulin and insulin analogues such as insulin glargine may vary considerably between different individuals or within the same individual. In a clinical study, symptoms of hypoglycaemia or counterregulatory hormone responses were similar after intravenous insulin glargine and intravenous human insulin in both healthy volunteers and type 1 diabetic patients. Clinical efficacy and safety In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed with the same frequency in both NPH insulin-treated and insulin glargine-treated groups. The effects of insulin glargine (once daily) on diabetic retinopathy were evaluated in a 5-year open-label NPH-controlled study (NPH given twice daily) that assessed retinopathy progression by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale using fundus photography in 1024 patients with type 2 diabetes. No significant difference in progression of diabetic retinopathy was observed when insulin glargine was compared with NPH insulin. ORIGIN (Outcome Reduction with Initial Glargine INtervention) was a multicentre, randomised, 2x2 factorial design study conducted in 12,537 participants at high cardiovascular (CV) risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes mellitus treated with ≤1 oral antidiabetic agent (88% of participants). Participants were randomised (1:1) to either insulin glargine (n=6,264) titrated to achieve FPG ≤95 mg/dL (5.3 mmol/L) or to standard care (n=6,273). The first co-primary efficacy endpoint was the time to first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke; the second co-primary efficacy endpoint was the time to first occurrence of any of the first co-primary endpoint events or revascularisation procedure (coronary, carotid, or peripheral) or hospitalisation for heart failure. Secondary endpoints included all-cause mortality and a composite microvascular outcome. Insulin glargine did not alter the relative risk of CV disease and CV mortality compared with standard care. There were no differences between insulin glargine and standard care for the two co-primary endpoints, for any component comprising the primary endpoints, for all-cause mortality, or for the composite microvascular outcome. The mean dose of insulin glargine at the end of the study was 0.42 U/kg. At baseline, participants had a median HbA1c of 6.4%. Median HbA1c during treatment ranged from 5.9–6.4% in the insulin glargine group and 6.2–6.6% in the standard care group over the follow-up period. The rate of severe hypoglycaemia (number of participants affected per 100 patient-years of exposure) was 1.05 in the insulin glargine group and 0.30 in the standard care group, while the rate of confirmed non-severe hypoglycaemia was 7.71 in the insulin glargine group and 2.44 in the standard care group. Over the 6-year duration of this study, 42% of participants in the insulin glargine group did not experience any hypoglycaemia. At the last on-treatment visit, mean body weight gain was 1.4 kg in the insulin glargine group and mean body weight loss was 0.8 kg in the standard care group. Paediatric population In a randomised controlled clinical trial, paediatric patients (aged 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks on a basal-bolus regimen where rapid-acting human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and human NPH insulin was administered once or twice daily. Similar effects on glycated haemoglobin 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. Furthermore, hypoglycaemia was less severe in the insulin glargine group. One hundred and forty-three patients treated with insulin glargine in this study continued insulin glargine treatment in an uncontrolled extension study with a mean follow-up of 2 years. No new safety signals were observed during this extended treatment with insulin glargine. A crossover study comparing insulin glargine plus insulin lispro versus NPH insulin plus rapid-acting human insulin (each treatment administered for 16 weeks in random order) was also conducted in 26 adolescents with type 1 diabetes aged 12 to 18 years. As in the paediatric study mentioned above, fasting plasma glucose reduction from baseline was greater in the insulin glargine group than in the NPH group. HbA1c changes from baseline were similar between both treatment groups; however, overnight blood glucose values were significantly higher in the insulin glargine/insulin lispro group than in the NPH/rapid-acting human insulin group, with a mean nadir of 5.4 mM versus 4.1 mM. Correspondingly, the incidence of nocturnal hypoglycaemia was 32% in the insulin glargine/insulin lispro group and 52% in the NPH/rapid-acting human insulin group. A 24-week parallel-group clinical study was conducted in 125 children with type 1 diabetes mellitus aged 2 to 6 years. The study compared insulin glargine administered once daily in the morning with NPH insulin administered once or twice daily as basal insulin. Both groups received bolus insulin before meals. The primary objective of demonstrating non-inferiority of insulin glargine to NPH in terms of all hypoglycaemic events was not met, and there was a trend towards an increased number of hypoglycaemic events with insulin glargine [rate ratio of insulin glargine vs. NPH (95% CI) = 1.18 (0.97–1.44)]. Glycated haemoglobin and glucose variability were comparable between both treatment groups. No new safety signals were observed in this clinical study.

⚠️ 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. Diabetic ketoacidosis ABASAGLAR is not the insulin of choice for the treatment of diabetic ketoacidosis.‍‍‍‍‍‍‍ Instead, intravenous rapid-acting insulin is recommended in such cases. Insulin requirement and dose adjustment In the case of inadequate glucose control or a tendency to hyperglycaemic or hypoglycaemic episodes, the patient's adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Transferring a patient to another type or brand of insulin must be done under strict medical supervision. Changes in strength, brand (manufacturer), type (rapid-acting, 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. 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. Due to sustained basal insulin supply with insulin glargine, less nocturnal but more early morning hypoglycaemia can be expected. Particular caution should be exercised, and intensified blood glucose monitoring is advisable in patients in whom hypoglycaemic episodes might be of particular clinical relevance, such as in patients with significant stenosis of the coronary arteries or of the blood vessels supplying the brain (risk of cardiac or cerebral complications of hypoglycaemia) as well as in patients with proliferative retinopathy, particularly if not treated with photocoagulation (risk of transient amaurosis following hypoglycaemia). Patients should be made aware of circumstances in which warning symptoms of hypoglycaemia are diminished. The warning symptoms of hypoglycaemia may be changed, be less pronounced, or be absent in certain risk groups. These include patients: in whom glycaemic control is markedly improved, in whom hypoglycaemia develops gradually, who are elderly, after transfer from animal insulin to human insulin, in whom autonomic neuropathy is present, with a long history of diabetes, suffering from a psychiatric illness, receiving concurrent treatment with certain other medicinal products (see section 4.5). Such situations may result in severe hypoglycaemia (and possibly loss of consciousness) before the patient becomes aware of hypoglycaemia. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. If normal or decreased values of glycated haemoglobin are noted, the possibility of recurrent, unrecognised (especially nocturnal) episodes of hypoglycaemia must be considered. Compliance of the patient with the dose and dietary regimen, correct insulin administration and awareness of hypoglycaemia symptoms are essential to reduce the risk of hypoglycaemia. Factors increasing the susceptibility to hypoglycaemia require particularly careful monitoring and may necessitate dose adjustment. These include: change in the injection area, improved insulin sensitivity (e.g. by removal of stress factors), unaccustomed, increased or prolonged physical activity, intercurrent illness (e.g. vomiting, diarrhoea), inadequate food intake, missed meals, alcohol consumption, certain uncompensated endocrine disorders (e.g. in hypothyroidism and in anterior pituitary or adrenocortical insufficiency), concomitant treatment with certain other medicinal products. Injection technique Patients must be instructed to rotate injection sites continuously in order 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 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 the change in the injection site, and dose adjustment of antidiabetic medicinal products may be considered. Intercurrent illness Intercurrent illness requires intensified metabolic monitoring. In many cases, urine ketone tests are indicated and often it is necessary to adjust the insulin dose. The insulin requirement is often increased. Patients with type 1 diabetes must continue to consume at least a small amount of carbohydrates on a regular basis, even if they are able to eat only little or no food, or are vomiting, etc., and they must never omit insulin entirely. Insulin antibodies Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulin antibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- or hypoglycaemia (see section 5.1). Medication errors Medication errors have been reported in which other insulins, particularly short-acting insulins, have been accidentally administered instead of insulin glargine. The insulin label must always be checked before each injection to avoid mix-ups between ABASAGLAR in pre-filled pen and other insulins. Combination of ABASAGLAR 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 ABASAGLAR and pioglitazone is considered. If the 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. Tempo Pen The Tempo Pen contains a magnet (see section 6.5), which may interfere with the function of implantable electronic medical devices such as pacemakers. The magnetic field has a range of approximately 1.5 cm. Sodium content This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially 'sodium-free'.

ABASAGLAR 100U/ML Solution for injection in pre-filled pen

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