Semglee® clinical trials have shown comparable efficacy and safety to reference insulin glargine1,2

Bioequivalence

Pharmacokinetics results show bioequivalence to reference product3

Semglee® and reference product insulins were present in the blood for at least 24 hours post-injection and reached similar maximum levels. The results ratios (Semglee®/reference product) for blood insulin level over a 30-hour period and maximum insulin concentration showed 90% confidence intervals (CI) within the 0.8 to 1.25 limits, indicating equivalence in terms of pharmacokinetics.3

Average serum insulin glargine levels measured over 30 hours following single injections of Semglee® and reference insulin glargine4

Pharmacodynamic data support the pharmacokinetics results3

Glucose-lowering action, as indicated by pharmacodynamic profiles (glucose infusion rate [GIR] over 30 hours post-injection) was considered as secondary endpoint.3

The smoothed GIR following single injections of Semglee® and reference insulin glargine showed similar time courses (low responding profiles with AUC GIR0-30 ≤50 (h*mg/kg/min) excluded). The pharmacodynamics results when comparing Semglee® and reference product reasonably supported the equivalent pharmacokinetics.3

Smoothed glucose infusion rates (GIR) over 30 hours following single injections of Semglee® and reference insulin glargine4

Efficacy

Similar efficacy to reference product in the treatment of hyperglycaemia in patients with type 2 diabetes mellitus2

An open-label randomised study comparing the efficacy of Semglee® with reference product in 560 patients with type 2 diabetes, insulin-naïve or not, found that Semglee® had equivalent efficacy to reference product in the treatment of hyperglycaemia.2

Clinical study design2
Multicentre, open-label, randomised, parallel group, 24-week trial.
560 patients with type 2 diabetes, with or without prior insulin use: 312 males and 248 females,
aged 18-65 years, BMI 18.5-40kg/m2.
HbA1c <10.5% (91 mmol/mol) or >7.5-10.5% (58-91 mmol/mol) for insulin-naïve patients at screening.
For the first 12-weeks, basal insulin was titrated without altering oral antidiabetic drug doses (the most common were metformin, 70.4%; glimepiride, 22.0%; glipizide, 14.6%; metformin hydrochloride, 11.1%). During the following 12-week maintenance period, all oral antidiabetic treatments were unchanged.

Results at 24 weeks showed that Semglee® lowered HbA1c and fasting plasma glucose (FPG) by a degree similar to that of the reference product. In all patients and insulin-naïve patients, no statistically significant differences were observed between groups in HbA1c profile over time or change in self-monitored blood glucose (SMBG) from baseline to week 24.2

Change in HbA1c from baseline to week 24 in all and insulin-naïve patients with Semglee® and reference insulin glargine2

Change in 7-point self-monitored blood glucose (SMBG) profile from baseline to week 24 in all and insulin-naïve patients with Semglee® and reference insulin glargine2

Similar efficacy to reference product in the treatment of hyperglycaemia in patients with type 1 diabetes mellitus1

An open-label randomized study comparing the efficacy of Semglee® with the reference product in 558 patients with type 1 diabetes found that Semglee® had equivalent efficacy to the reference insulin glargine in the treatment of hyperglycaemia.1

Clinical study design1
Multicentre, open-label, randomised, parallel group, 52-week trial.
558 patients with type 1 diabetes, 336 males and 222 females, aged 18-65 years,
BMI 18.5-35 kg/m2.
Treated with once-daily insulin glargine for more than 3 months and with HbA1c ≤9.5% at screening.
Patients began a 6-week run-in period and were titrated with first reference insulin glargine and then insulin lispro, as needed, to ensure good diabetes control as determined by the investigator.
At randomisation, there was a 1:1 (unit for unit) conversion of reference insulin glargine to Semglee® (100 U/mL of insulin glargine) and of prestudy mealtime insulin to insulin lispro.

The mean change in HbA1c from baseline to week 24 (primary endpoint) was 0.14% compared to 0.11% with reference insulin glargine, with a difference in change in HbA1c from baseline to week 24 between the 2 treatment groups of 0.03%, demonstrating the non-inferiority of Semglee®.1

The difference in change in HbA1c from baseline to week 52 (-0.05%) showed again equivalent efficacy between the 2 treatments.1

Mean change in HbA1c from baseline at week 24 and 52

No statistically significant differences were observed in the mean change in FPG from baseline to week 52 between the 2 treatment groups. At week 24, there was a transient statistically significant difference (p=0.017) with –0.81 mmol/L for Semglee® and +0.09 mmol/L for reference insulin glargine.1

Mean change in fasting plasma glucose from baseline at week 24 and 52

Safety

Proven safety profile in patients with diabetes mellitus, no significant difference in safety and tolerability compared to reference product.2

Hypoglycaemia is a potential treatment complication with insulins in general, but it is also important that insulin therapy does not have detrimental effects on other aspects of patients’ health.

Proven safety profile in patients with type 2 diabetes2

The overall and nocturnal rates of hypoglycaemia (episodes/30 days) were similar between Semglee® and the reference insulin glargine throughout the 24-week. No statistically significant differences in hypoglycaemia rate or incidence profile were observed between the Semglee® and the reference insulin glargine groups at any visit.

Incidence of overall (anytime) and nocturnal hypoglycaemia rates for Semglee®-
and the reference insulin glargine-treated patients by study visit2

Adverse events with Semglee® are similar to the reference product2

The incidence of treatment emergent adverse events (TEAEs) was generally similar for patients on Semglee® and patients on the reference insulin glargine: 64.1% and 58.2%, respectively, experienced at least one TEAE over 24 weeks. Overall, the majority of TEAEs were mild to moderate in severity. Only 4 patients in the Semglee® group and 2 patients in the reference insulin glargine group experienced a local or systemic reaction during the treatment period.2

Frequency of TEAEs over 24 weeks of treatment with Semglee® or reference insulin glargine.

Parameter, n (%) Semglee® Reference
Product
Patients with ≥1 TEAE 177 (64.1) 164 (58.2)
Patients with ≥1 TEAE of grade ≥3 8 (2.9) 13 (4.6)
Patients who discontinued because of TEAE 3 (1.1) 0 (0)
TEAEs occurring in ≥2% of patients in either treatment group:
Hypoglycaemia 75 (27.2) 66 (23.4)
Upper respiratory tract infection 17 (6.2) 15 (5.3)
Urinary tract infection 12 (4.3) 8 (2.8)
Nasopharyngitis 10 (3.6) 13 (4.6)
Headache 8 (2.9) 10 (3.5)
Sinusitis 8 (2.9) 4 (1.4)
Back pain 7 (2.5) 6 (2.1)
Nausea 6 (2.2) 4 (1.4)
Influenza 6 (2.2) 3 (1.1)
Hypertension 6 (2.2) 2 (0.7)
Tremor 6 (2.2) 1 (0.4)
Bronchitis 5 (1.8) 7 (2.5)
Cough 4 (1.4) 10 (3.5)
Dizziness 4 (1.4) 7 (2.5)
Edema, peripheral 2 (0.7) 6 (2.1)

TEAE: Treatment-emergent adverse event.
p>0.05 for all differences in safety outcomes between groups.

Proven safety profile in patients with type 1 diabetes.1

Rates of TEAEs were similar between Semglee® and reference insulin glargine at week 52. In total, 225 (80.4%) patients in the Semglee® group and 239 (86.0%) patients in the reference insulin glargine group experienced ≥1 TEAE during the 52-week treatment period.1

The most common TEAE was hypoglycaemia, which occurred in 154 (55.0%) and 170 (61.2%) patients treated with Semglee® and reference insulin glargine, respectively, with 11 (3.9%) and 13 patients (4.7%) reporting at least 1 severe hypoglycaemic event, respectively. Overall, anytime and nocturnal hypoglycaemic rates (episodes/30 days) and incidence profiles were comparable between the 2 treatment groups throughout the study.1

Incidence of anytime and nocturnal hypoglycaemic events (SMBG ≤70 mg/dL) by visit and treatment group

Overall, the results of the immunogenicity profiles were comparable between Semglee® and reference insulin glargine. Although a statistically significant difference in the change in total antidrug antibodies was observed with reference insulin glargine at week 52, no statistically significant differences between the 2 treatment groups were observed for any type of insulin antibodies at any of the visits during the treatment period.1

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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