Semglee® – an approved
biosimilar of reference
insulin glargine1

What is Semglee®?

  • Semglee® is a once-daily long-acting insulin analogue (100 units/ml).2
  • Semglee® is an approved biosimilar of reference insulin glargine.1
  • Semglee® offers similar clinical benefits compared with the reference insulin glargine including duration of action, glucose-lowering effectiveness (HbA1c and fasting plasma glucose) and rate of hypoglycaemia.3,4
  • Semglee® is available as a solution for injection containing 100 U/ml x 3 ml (i.e. 300U) in prefilled pens.2

Therapeutic Indication2

Semglee® is indicated for the treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.2

How does Semglee® work?2

Insulin glargine is a human insulin analogue designed to have a low solubility at neutral pH. It is completely soluble at the acidic pH of the Semglee® injection solution (pH 4). After injection into the subcutaneous tissue, the acidic solution is neutralised leading to formation of micro-precipitates 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 glargine is metabolised into 2 active metabolites M1 and M2.

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 the one of human insulin.

Insulin-like growth factor 1 (IGF-1) receptor binding: The affinity of insulin glargine for the human IGF-1 receptor is approximately 5 to 8-fold greater than that of human insulin (but approximately 70 to 80-fold lower than the one of IGF-1), whereas M1 and M2 bind the IGF-1 receptor with slightly lower affinity compared to human insulin.

The total therapeutic insulin concentration (insulin glargine and its metabolites) found in type 1 diabetic patients was markedly lower than what would be required for a half-maximal occupation of the IGF-1 receptor and the subsequent activation of the mitogenic-proliferative pathway initiated by the IGF-1 receptor. Physiological concentrations of endogenous IGF-1 may activate the mitogenic-proliferative pathway; however, the therapeutic concentrations found in insulin therapy, including in Semglee® therapy, are considerably lower than the pharmacological concentrations required to activate the IGF-1 pathway.

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, intravenous insulin glargine and human insulin have been 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 subcutaneous insulin glargine was slower than with human NPH insulin, its effect profile was smooth and peakless, and the duration of its effect was prolonged.

The following graph shows the results from a study in patients:

*Determined as amount of glucose infused to maintain constant plasma glucose levels (hourly mean values)

The longer duration of action of subcutaneous insulin glargine is directly related to its slower rate of absorption and supports once daily administration.

The time course of action of insulin and insulin analogues such as insulin glargine may vary considerably in different individuals or within the same individual.

In a clinical study, symptoms of hypoglycaemia or counter-regulatory hormone responses were similar after intravenous insulin glargine and human insulin both in healthy volunteers and patients with type 1 diabetes.

In clinical studies, antibodies that cross-react with human insulin and insulin glargine were observed with the same frequency in both NPH-insulin and insulin glargine treatment groups.

Effects of insulin glargine (once-daily) on diabetic retinopathy were evaluated in an open-label 5-year NPH-controlled study (NPH given bid) in 1024 type 2 diabetic patients in which progression of retinopathy by 3 or more 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.

Insulin glargine was compared to standard care on the risk of cardiovascular disease (CV) or CV death in the ORIGIN6 (Outcome Reduction with Initial Glargine Intervention) study. 12,537 subjects at high cardiovascular risk with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (12% of participants) or type 2 diabetes mellitus treated with ≤1 antidiabetic oral agent (88% of participants) were randomised (6,264 to receive insulin glargine, titrated to reach FPG ≤95 mg/dl (5.3 mmol/L), or 6,273 to receive standard care). Patients were followed for a median 6.2 years.2

The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from CV causes and these events plus revascularization or hospitalisation for heart failure. Microvascular outcomes, incident diabetes, hypoglycaemia, weight and cancers were also compared between groups.

After a median of 6.2 years follow-up, insulin glargine had a neutral effect on cardiovascular outcomes and cancers compared to standard care.

The rates of severe hypoglycaemia (affected participants per 100 participant years of exposure) were 1.05 for insulin glargine and 0.30 for standard care group and the rates of confirmed non-severe hypoglycaemia were 7.71 for insulin glargine and 2.44 for standard care group. Over the course of the study, 42% of the insulin glargine group did not experience any hypoglycaemia. Insulin glargine showed a reduction in new-onset diabetes compared to standard care.6

At the last on-treatment visit, there was a mean increase in body weight from baseline of 1.4 kg in the insulin glargine group and a mean decrease of 0.8 kg in the standard care group.2

Paediatric population2: In a randomised, controlled clinical study, paediatric patients (age range 6 to 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 glycohemoglobin 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 and there was less severe hypoglycaemia in the insulin glargine group.

A 24-week parallel group study was conducted in 125 children with type 1 diabetes mellitus aged 2 to 6 years, comparing insulin glargine given once daily in the morning to NPH insulin given once or twice daily as basal insulin. Both groups received bolus insulin before meals.

The primary aim of demonstrating non-inferiority of insulin glargine to NPH in all hypoglycaemia was not met and there was a trend to an increase of hypoglycaemic events with insulin glargine [insulin glargine: NPH rate ratio (95% CI) = 1.18 (0.97-1.44)]. Glycohemoglobin and glucose variabilities were comparable in both treatment groups. No new safety signals were observed in this study.

Comparison of Excipients

Excipients Semglee® Reference
product
Zinc Chloride
Metacresol
Glycerol
Hydrochloric acid (for pH adjustment)
Sodium Hydroxide (for pH adjustment)
Water for injection

The excipients present in the solution of Semglee® are the same as the ones in the reference product2,5

References:

Adverse Events Reporting

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare providers are asked to report any suspected adverse reactions. Reporting forms and information can be found at http://www.mhra.gov.uk/yellowcard. In order to support effective tracking and traceability of biologics including biosimilars, it is recommended that the brand name and batch number are recorded and used when reporting adverse events. You can also report adverse events direct to the marketing authorisation holder at ukpharmacovigilance@mylan.com.

Semglee® (Insulin glargine) 100 units/ml solution for injection in pre-filled pen

Prescribing information

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Indication: Semglee® is indicated in the treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above. Presentation: Each ml contains 100 units insulin glargine* (equivalent to 3.64 mg). Each pen contains 3 ml of solution for injection, equivalent to 300 units. Dosage and administration: Semglee® (insulin glargine) has a prolonged duration of action. It should be administered once daily at any time but at the same time each day. The pre filled pen delivers insulin in increments of 1 unit up to a maximum single dose of 80 units. The dose regimen (dose and timing) should be individually adjusted. In patients with type 2 diabetes mellitus, Semglee® can also be given together with orally active antidiabetic medicinal products. The potency of Semglee® is stated in units and these units are exclusive to Semglee®. Special population: Elderly population (≤ 65 years old): progressive deterioration of renal function may lead to a steady decrease in insulin requirements. Renal impairment: insulin requirements may be diminished due to reduced insulin metabolism. Hepatic impairment: insulin requirements may be diminished due to reduced capacity for gluconeogenesis and reduced insulin metabolism. Paediatric population: For adolescents and children aged 2 years and older patients, the dose regimen (dose and timing) should be individually adjusted. For children below 2 years of age the safety and efficacy of Semglee® have not been established. No data are available. Switch from other insulins to Semglee® When switching from a treatment regimen with an intermediate or long acting insulin to a regimen with Semglee®, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast acting insulin analogues or the dose of oral antidiabetic medicinal products). Switch from twice daily NPH insulin to Semglee®: To reduce the risk of nocturnal and early morning hypoglycaemia, daily dose of once daily basal insulin should be reduced by 20-30% during the first weeks of treatment. Switch from insulin glargine 300 units/ml to Semglee®: Semglee® and insulin glargine 300 units/ml are not bioequivalent and are not directly interchangeable. To reduce the risk of hypoglycemia in this group, Semglee® dose should be reduced by approximately 20%. During the first weeks increase mealtime insulin, after this period the regimen should be adjusted individually. Close metabolic monitoring is recommended during the switch and in the initial weeks thereafter. A further adjustment in dose regimen may become necessary with improved metabolic control, change of timing of insulin, patient weight or life style changes. Patients with high insulin doses because of antibodies to human insulin may experience an improved insulin response with Semglee®. Method of administration Semglee® is administered subcutaneously only. Injection sites must be rotated within a given injection area from one injection to the next. Semglee® must not be mixed with any other insulin or diluted. Before using the pre filled pen, the instructions for use included in the package leaflet must be read carefully (see section 6.6). Contraindications: Known hypersensitivity to the active substances or to any of the excipients. Warnings and precautions: Warnings: Semglee® is not the insulin of choice for the treatment of diabetic ketoacidosis. In case of insufficient glucose control or a tendency to hyper- 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. Changes in insulin strength, manufacturer, type, origin, method of manufacture and/or method of administration may result in the need for a change in insulin dose or an adjustment in concomitant oral antidiabetic treatment. Hypoglycaemia Due to more sustained basal insulin supply with Semglee®, less nocturnal but more early morning hypoglycaemia can be expected. Intercurrent illness In many cases urine tests for ketones 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 Rare chance of antibodies formation, may require insulin dose adjustment to avoid hyper- or hypoglycaemia. Handling of the pen Before using Semglee® pen, the instructions for use included in the package leaflet must be read carefully. Semglee® pen has to be used as recommended in the instructions for use. Medication errors Insulin label must always be checked before each injection to avoid medication errors between insulin glargine and other insulins. Interaction with other medicinal products: Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs when used with Semglee®. Substances that may enhance the blood glucose lowering effect include oral antidiabetic medicinal products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, pentoxifylline, propoxyphene, salicylates and sulfonamide antibiotics. Substances that may reduce the blood glucose lowering effect include corticosteroids, danazol, diazoxide, diuretics, glucagon, isoniazid, oestrogens and progestogens, phenothiazine derivatives, somatropin, sympathomimetic medicinal products (e.g. epinephrine [adrenaline], salbutamol, terbutaline), thyroid hormones, atypical antipsychotic medicinal products (e.g. clozapine and olanzapine) and protease inhibitors. Beta blockers, clonidine, lithium salts or alcohol may either potentiate or weaken the blood glucose lowering effect of insulin. Pentamidine may cause hypoglycaemia, which may sometimes be followed by hyperglycaemia. Pregnancy and lactation: Pregnancy For insulin glargine no clinical data on exposed pregnancies from controlled clinical studies are available. A large amount of data on pregnant women (more than 1000 pregnancy outcomes) indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor feto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity. The use of Semglee® may be considered during pregnancy, if clinically needed. The use of Semglee® may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. Breast feeding It is unknown whether insulin glargine is excreted in human milk. Women may require adjustments in insulin dose and diet. Effects on ability to drive and use machines: The patient's ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. Undesirable effects: Very common: Hypoglycaemia. Common: Lipohypertrophy, Injection site reactions Uncommon: Lipoatrophy. For rare and very rare undesirable effects, please refer to SmPC. Name and Address of Marketing Authorisation Holder: Mylan S.A.S., 117 allée des Parcs, 69800 Saint Priest, France. Marketing Authorisation Number: EU/1/18/1270/003 Basic NHS price: 3ml x 5 pens=£29.99 Legal Category: POM Date of Last Revision: October 2018

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. and from Mylan Medical Information, Building 4, Trident Place, Hatfield Business Park, Mosquito Way, Hatfield, Hertfordshire, AL10 9BW, phone no. 01707 853000, Email: info@mylan.co.uk

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare providers are asked to report any suspected adverse reactions. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. In order to support effective tracking and traceability of biologics including biosimilars, it is recommended that the brand name and batch number are recorded and used when reporting adverse events. Adverse events should be reported to Pharmacovigilance, Mylan, Building 4, Trident Place, Hatfield Business Park, Mosquito Way, Hatfield, Hertfordshire, AL10 9UL, on phone no. 0800 121 8267, Email: ukpharmacovigilance@mylan.com

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