TRESIBA 100U / ml injection for pre-filled pen medication leaflet

Tresiba 100 units/mL solution for injection in pre-filled pen

Tresiba 200 units/mL solution for injection in pre-filled pen

Tresiba 100 units/mL solution for injection in cartridge

Tresiba 100 units/mL solution for injection in pre-filled pen

One pre-filled pen contains 300 units of insulin degludec in 3 mL solution.

1 mL solution contains 100 units insulin degludec* (equivalent to 3.66 mg insulin degludec).

Tresiba 200 units/mL solution for injection in pre-filled pen

One pre-filled pen contains 600 units of insulin degludec in 3 mL solution.

1 mL solution contains 200 units insulin degludec* (equivalent to 7.32 mg insulin degludec).

Tresiba 100 units/mL solution for injection in cartridge

One cartridge contains 300 units of insulin degludec in 3 mL solution.

1 mL solution contains 100 units insulin degludec* (equivalent to 3.66 mg insulin degludec).

*Produced in Saccharomyces cerevisiae by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Tresiba 100 units/mL solution for injection in pre-filled pen

Solution for injection (FlexTouch).

Tresiba 200 units/mL solution for injection in pre-filled pen

Solution for injection (FlexTouch).

Tresiba 100 units/mL solution for injection in cartridge

Solution for injection (Penfill).

Clear, colourless, neutral solution.

Treatment of diabetes mellitus in adults, adolescents and children from the age of 1 year.

This medicinal product is a basal insulin for once-daily subcutaneous administration at any time of theday, preferably at the same time every day.

The potency of insulin analogues, including insulin degludec, is expressed in units. One (1) unit ofinsulin degludec corresponds to 1 international unit of human insulin, 1 unit of insulin glargine(100 units/mL), or 1 unit of insulin detemir.

In patients with type 2 diabetes mellitus, this medicinal product can be administered alone or in anycombination with oral antidiabetic medicinal products, GLP-1 receptor agonists and bolus insulin (seesection 5.1).

In type 1 diabetes mellitus, Tresiba must be combined with short-/rapid-acting insulin to covermealtime insulin requirements.

Tresiba is to be dosed in accordance with the individual patient’s needs. It is recommended to optimiseglycaemic control via dose adjustment based on fasting plasma glucose.

Adjustment of dose may be necessary if patients undertake increased physical activity, change theirusual diet or during concomitant illness.

Tresiba 100 units/mL and Tresiba 200 units/mL solution for injection in a pre-filled pen

Tresiba is available in two strengths. For both, the needed dose is dialled in units. The dose steps,however, differ between the two strengths of the medicinal product.

* With Tresiba 100 units/mL a dose of 1-80 units per injection, in steps of 1 unit, can beadministered.

* With Tresiba 200 units/mL a dose of 2-160 units per injection, in steps of 2 units, can beadministered. The dose is provided in half the volume of 100 units/mL basal insulin products.

The dose counter shows the number of units regardless of strength and no dose conversion should bedone when transferring a patient to a new strength.

Flexibility in dosing time

On occasions when administration at the same time of the day is not possible, Tresiba allows forflexibility in the timing of insulin administration (see section 5.1). A minimum of 8 hours betweeninjections should always be ensured. There is no clinical experience with flexibility in dosing time of

Tresiba in children and adolescents.

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-dailydosing schedule.

The recommended daily starting dose is 10 units followed by individual dosage adjustments.

Patients with type 1 diabetes mellitus

Tresiba is to be used once daily with mealtime insulin and requires subsequent individual dosageadjustments.

Transfer from other insulin medicinal products

Close glucose monitoring is recommended during the transfer and in the following weeks. Doses andtiming of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetictreatment may need to be adjusted.

For patients with type 2 diabetes taking once-daily basal, basal-bolus, premix or self-mixed insulintherapy, changing the basal insulin to Tresiba can be done unit-to-unit based on the previous basalinsulin dose followed by individual dosage adjustments.

A dose reduction of 20% based on the previous basal insulin dose followed by individual dosageadjustments should be considered when

- transferring to Tresiba from twice-daily basal insulin

- transferring to Tresiba from insulin glargine (300 units/mL)

Patients with type 1 diabetes mellitus

For patients with type 1 diabetes a dose reduction of 20% based on the previous basal insulin dose orbasal component of a continuous subcutaneous insulin infusion regimen should be considered withsubsequent individual dosage adjustments based on the glycaemic response.

Use of Tresiba in combination with GLP-1 receptor agonists in patients with type 2 diabetes mellitus

When adding Tresiba to GLP-1 receptor agonists, the recommended daily starting dose is 10 unitsfollowed by individual dosage adjustments.

When adding GLP-1 receptor agonists to Tresiba, it is recommended to reduce the dose of Tresiba by20% to minimise the risk of hypoglycaemia. Subsequently, dosage should be adjusted individually.

Tresiba can be used in elderly. Glucose monitoring is to be intensified and the insulin dose adjusted onan individual basis (see section 5.2).

Tresiba can be used in renal and hepatic impaired patients. Glucose monitoring is to be intensified andthe insulin dose adjusted on an individual basis (see section 5.2).

There is no clinical experience with the use of this medicinal product in children below the age of1 year. This medicinal product can be used in adolescents and children from the age of 1 year (seesection 5.1). When changing basal insulin to Tresiba, dose reduction of basal and bolus insulin needsto be considered on an individual basis in order to minimise the risk of hypoglycaemia (see section4.4).

Subcutaneous use only.

Tresiba must not be administered intravenously as it may result in severe hypoglycaemia.

This medicinal product must not be administered intramuscularly as it may change the absorption.

This medicinal product must not be used in insulin infusion pumps.

Tresiba must not be drawn from the cartridge of the pre-filled pen into a syringe (see section 4.4).

Tresiba is administered subcutaneously by injection in the thigh, the upper arm or the abdominal wall.

Injection sites should always be rotated within the same region in order to reduce the risk oflipodystrophy and cutaneous amyloidosis (see sections 4.4 and 4.8).

Patients should be instructed to always use a new needle. The re-use of insulin pen needles increasesthe risk of blocked needles, which may cause under- or overdosing. In the event of blocked needles,patients must follow the instructions described in the instructions for use accompanying the packageleaflet (see section 6.6).

Tresiba 100 units/mL and Tresiba 200 units/mL solution for injection in a pre-filled pen

Tresiba comes in a pre-filled pen (FlexTouch) designed to be used with NovoFine or NovoTwistinjection needles.

- The 100 units/mL pre-filled pen delivers 1-80 units in steps of 1 unit.

- The 200 units/mL pre-filled pen delivers 2-160 units in steps of 2 units.

Tresiba 100 units/mL solution for injection in a cartridge

Tresiba comes in a cartridge (Penfill) designed to be used with Novo Nordisk insulin delivery systemsand NovoFine or NovoTwist injection needles.

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

Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement (seesections 4.5, pct. 4.8 and 4.9).

In children, care should be taken to match insulin doses (especially in basal-bolus regimens) with foodintake and physical activities in order to minimise the risk of hypoglycaemia.

Patients whose blood glucose control is greatly improved (e.g. by intensified insulin therapy) mayexperience a change in their usual warning symptoms of hypoglycaemia and must be advisedaccordingly. Usual warning symptoms may disappear in patients with long-standing diabetes.

Concomitant illness, especially infections and fever, usually increases the patient's insulinrequirement. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary orthyroid gland may require changes in the insulin dose.

As with other basal insulin products, the prolonged effect of Tresiba may delay recovery fromhypoglycaemia.

Administration of rapid-acting insulin is recommended in situations with severe hyperglycaemia.

Inadequate dosing and/or discontinuation of treatment in patients requiring insulin may lead tohyperglycaemia and potentially to diabetic ketoacidosis. Furthermore, concomitant illness, especiallyinfections, may lead to hyperglycaemia and thereby cause an increased insulin requirement.

Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. Theyinclude thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, drymouth, and loss of appetite as well as acetone odour of breath. In type 1 diabetes mellitus, untreatedhyperglycaemic events eventually lead to diabetic ketoacidosis, which is potentially lethal.

Transfer from other insulin medicinal products

Transferring a patient to another type, brand or manufacturer of insulin must be done under medicalsupervision and may result in the need for a change in dosage.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulinabsorption and worsened glycaemic control following insulin injections at sites with these reactions. Asudden 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 from an affected to anunaffected area, and dose adjustment of antidiabetic medications may be considered.

Combination of pioglitazone and insulin medicinal products

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 mindif treatment with the combination of pioglitazone and Tresiba is considered. If the combination isused, 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.

Eye disorder

Intensification of insulin therapy with abrupt improvement in glycaemic control may be associatedwith temporary worsening of diabetic retinopathy, while long-term improved glycaemic controldecreases the risk of progression of diabetic retinopathy.

Avoidance of medication errors

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between the two different strengths of Tresiba as well as other insulin products.

Patients must visually verify the dialled units on the dose counter of the pen. Therefore, therequirement for patients to self-inject is that they can read the dose counter on the pen. Patients whoare blind or have poor vision must be instructed to always get help/assistance from another person whohas good vision and is trained in using the insulin device.

To avoid dosing errors and potential overdose, patients and healthcare professionals should never usea syringe to draw the medicinal product from the cartridge in the pre-filled pen.

In the event of blocked needles, patients must follow the instructions described in the instructions foruse accompanying the package leaflet (see section 6.6).

Insulin administration may cause insulin antibodies to form. In rare cases, the presence of such insulinantibodies may necessitate adjustment of the insulin dose in order to correct a tendency to hyper- orhypoglycaemia.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially‘sodium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

A number of medicinal products are known to interact with glucose metabolism.

The following substances may reduce the insulin requirement

Oral antidiabetic medicinal products, GLP-1 receptor agonists, monoamine oxidase inhibitors(MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroidsand sulfonamides.

The following substances may increase the insulin requirement

Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growthhormone and danazol.

Beta-blockers may mask the symptoms of hypoglycaemia.

Octreotide/lanreotide may either increase or decrease the insulin requirement.

Alcohol may intensify or reduce the hypoglycaemic effect of insulin.

The use of Tresiba in pregnant women with diabetes has been investigated in an interventional trial(see section 5.1). A moderate amount of clinical trial and post-marketing data in pregnant women(more than 400 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity. Animalreproduction studies have not revealed any difference between insulin degludec and human insulinregarding embryotoxicity and teratogenicity.

The treatment with Tresiba may be considered during pregnancy, if clinically needed.

In general, intensified blood glucose control and monitoring of pregnant women with diabetes arerecommended throughout pregnancy and when contemplating pregnancy. Insulin requirements usuallydecrease in the first trimester and increase subsequently during the second and third trimesters. Afterdelivery, insulin requirements usually return rapidly to pre-pregnancy values. Careful monitoring ofglucose control is recommended and the insulin dose adjusted on an individual basis.

There is no clinical experience with Tresiba during breast-feeding. In rats, insulin degludec wassecreted in milk; the concentration in milk was lower than in plasma.

It is unknown whether insulin degludec is excreted in human milk. No metabolic effects areanticipated in the breast-fed newborn/infant.

Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility.

This medicinal product has no or negligible influence on the ability to drive and use machines.

However, the patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia.

This may constitute a risk in situations where these abilities are of special importance (e.g. driving acar or using machines).

Patients must be advised to take precautions to avoid hypoglycaemia while driving. This is particularlyimportant in those who have reduced or absent awareness of the warning signs of hypoglycaemia orhave frequent episodes of hypoglycaemia. The advisability of driving should be considered in thesecircumstances.

The most frequently reported adverse reaction during treatment is hypoglycaemia (see section‘Description of selected adverse reactions’ below).

Adverse reactions listed below are based on clinical trial data and classified according to MedDRA

System Organ Class. Frequency categories are defined according to the following convention: Verycommon (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to<1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

System organ class Frequency Adverse reaction

Immune system disorders Rare Hypersensitivity

Urticaria

Metabolism and nutrition disorders Very common Hypoglycaemia

Skin and subcutaneous tissue disorders Uncommon Lipodystrophy

Not known Cutaneous amyloidosis†

General disorders and administration site conditions Common Injection site reactions

Uncommon Peripheral oedema† ADR from postmarketing sources.

With insulin preparations, allergic reactions may occur. Immediate-type allergic reactions to eitherinsulin itself or the excipients may potentially be life-threatening.

With Tresiba, hypersensitivity (manifested with swelling of tongue and lips, diarrhoea, nausea,tiredness and itching) and urticaria were reported rarely.

Hypoglycaemia may occur if the insulin dose is too high in relation to the insulin requirement. Severehypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary orpermanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occursuddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness,unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger,vision changes, headache, nausea and palpitation.

Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at theinjection site and delay local insulin absorption. Continuous rotation of the injection site within thegiven injection area may help to reduce or prevent these reactions (see section 4.4).

Injection site reactions (including injection site haematoma, pain, haemorrhage, erythema, nodules,swelling, discolouration, pruritus, warmth and injection site mass) occurred in patients treated with

Tresiba. These reactions are usually mild and transitory and they normally disappear during continuedtreatment.

Tresiba has been administered to children and adolescents up to 18 years of age for the investigationof pharmacokinetic properties (see section 5.2). Safety and efficacy have been demonstrated in a longterm trial in children aged 1 to less than 18 years. The frequency, type and severity of adversereactions in the paediatric population do not indicate differences to the experience in the generaldiabetes population (see section 5.1).

Based on results from clinical trials, the frequency, type and severity of adverse reactions observed inelderly and in patients with renal or hepatic impairment do not indicate any differences to the broaderexperience in the general population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A specific overdose for insulin cannot be defined. However, hypoglycaemia may develop oversequential stages if a patient is dosed with more insulin than required:

* Mild hypoglycaemic episodes can be treated by oral administration of glucose or other productscontaining sugar. It is therefore recommended that the patient always carries glucose-containingproducts.

* Severe hypoglycaemic episodes, where the patient is not able to treat himself, can be treatedwith glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, orwith glucose given intravenously by a healthcare professional. Glucose must be givenintravenously if the patient does not respond to glucagon within 10 to 15 minutes. Uponregaining consciousness, administration of oral carbohydrates is recommended for the patient inorder to prevent a relapse.

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting.

ATC code: A10AE06.

Insulin degludec binds specifically to the human insulin receptor and results in the samepharmacological effects as human insulin.

The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following thebinding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucoseoutput from the liver.

Tresiba is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting ina depot from which insulin degludec is continuously and slowly absorbed into the circulation leadingto a flat and stable glucose-lowering effect of Tresiba (see figure 1). During a period of 24 hours withonce-daily treatment, the glucose-lowering effect of Tresiba, in contrast to insulin glargine, was evenlydistributed between the first and second 12 hours (AUCGIR,0-12h,SS/AUCGIR,total,SS = 0.5).

Time since injection (hours)

Treatment IDeg 0.6 units/kg

Figure 1 Glucose infusion rate profile, smoothed, steady state - Mean profile 0-24 hours - IDeg100 units/mL 0.6 units/kg - Trial 1987

The duration of action of Tresiba is beyond 42 hours within the therapeutic dose range.

Steady state will occur after 2-3 days of dose administration.

The day-to-day variability, expressed as the coefficient of variation, in glucose-lowering effect duringone dosing interval of 0-24 hours at steady state (AUCGIR,τ,SS) is 20% for insulin degludec, which issignificantly lower than for insulin glargine (100 units/mL).

The total glucose-lowering effect of Tresiba increases linearly with increasing doses.

The total glucose-lowering effect is comparable for Tresiba 100 units/mL and 200 units/mL afteradministration of the same doses of the two products.

There is no clinically relevant difference in the pharmacodynamics of this medicinal product betweenelderly and younger adult patients.

Clinical efficacy and safety11 multinational clinical trials of 26 or 52 weeks’ duration were conducted as controlled, open-label,randomised, parallel, treat-to-target trials exposing 4,275 patients to Tresiba (1,102 in type 1 diabetes

Glucose Infusion Rate (mg/(kg*min))mellitus and 3,173 in type 2 diabetes mellitus).

In the open-label trials the effect of Tresiba was tested in patients with type 1 diabetes mellitus (Table2), in insulin naïve patients (insulin initiation in type 2 diabetes mellitus, Table 3) and in previousinsulin users (insulin intensification in type 2 diabetes mellitus, Table 4) with fixed as well as flexibledosing time (Table 5), and the reduction in HbA1c from baseline to end of trial was confirmed to benon-inferior in all trials against all comparators (insulin detemir and insulin glargine (100 units/mL)).

While improvements in HbA1c were non-inferior compared to other insulin products, against sitagliptin

Tresiba was statistically significantly superior in reducing HbA1c (Table 4).

In a prospectively planned meta-analysis across seven open-label treat-to-target confirmatory trials inpatients with type 1 and type 2 diabetes mellitus, Tresiba was superior in terms of a lower number oftreatment-emergent confirmed hypoglycaemic episodes (driven by a benefit in type 2 diabetesmellitus, see Table 1) and nocturnal confirmed hypoglycaemic episodes compared to insulin glargine(100 units/ml) (administered according to label). The reduction in hypoglycaemia was achieved at alower average FPG level with Tresiba than with insulin glargine.

Table 1 Hypoglycaemia meta-analysis outcomes

Confirmed hypoglycaemiaa

Estimated risk ratio (Insulin degludec/Insulin glargine) Total Nocturnal

Type 1 + Type 2 diabetes mellitus (pooled) 0.91* 0.74*

Maintenance period b 0.84* 0.68*

Geriatric patients ≥65 years 0.82 0.65*

Type 1 diabetes mellitus 1.10 0.83

Maintenance period b 1.02 0.75*

Type 2 diabetes mellitus 0.83* 0.68*

Maintenance period b 0.75* 0.62*

Basal only therapy in previously insulin-naïve 0.83* 0.64*

*Statistically significant a Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L orby the patient needing third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnightand 6 a.m. b Episodes from week 16.

There is no clinically relevant development of insulin antibodies after long-term treatment with

Tresiba.

Table 2 Results from open-label clinical trials in type 1 diabetes mellitus52 weeks of treatment 26 weeks of treatment

Tresiba1 Insulin Tresiba1 Insulinglargine detemir1(100 units/mL)1

N 472 157 302 153

HbA1c (%)

End of trial 7.3 7.3 7.3 7.3

Mean change -0.40 -0.39 -0.73 -0.65

Difference: -0.01 [-0.14; 0.11] Difference: -0.09[-0.23; 0.05]

FPG (mmol/L)

End of trial 7.8 8.3 7.3 8.9

Mean change -1.27 -1.39 -2.60 -0.62

Difference: -0.33 [-1.03; 0.36] Difference: -1.66 [-2.37; -0.95]

Rate of hypoglycaemia (per Patient year of exposure)

Severe 0.21 0.16 0.31 0.39

Confirmed2 42.54 40.18 45.83 45.69

Ratio: 1.07 [0.89; 1.28] Ratio: 0.98 [0.80; 1.20]

Nocturnal confirmed2 4.41 5.86 4.14 5.93

Ratio: 0.75 [0.59; 0.96] Ratio: 0.66 [0.49; 0.88]1 In a once-daily regimen + insulin aspart to cover mealtime insulin requirements2 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needingthird party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table 3 Results from open-label clinical trials in insulin naïve type 2 diabetes mellitus (insulininitiation)52 weeks of treatment 26 weeks of treatment

Tresiba1 Insulin Tresiba1 Insulinglargine glargine(100 units/mL)1 (100 units/mL)1

N 773 257 228 229

HbA1c (%)

End of trial 7.1 7.0 7.0 6.9

Mean change -1.06 -1.19 -1.30 -1.32

Difference: 0.09 [-0.04; 0.22] Difference: 0.04 [-0.11; 0.19]

FPG (mmol/L)

End of trial 5.9 6.4 5.9 6.3

Mean change -3.76 -3.30 -3.70 -3.38

Difference: -0.43 [-0.74; -0.13] Difference: -0.42 [-0.78; -0.06]

Rate of hypoglycaemia (per patient year of exposure)

Severe 0 0.02 0 0

Confirmed2 1.52 1.85 1.22 1.42

Ratio: 0.82 [0.64; 1.04] Ratio: 0.86 [0.58; 1.28]

Nocturnal confirmed2 0.25 0.39 0.18 0.28

Ratio: 0.64 [0.42; 0.98] Ratio: 0.64 [0.30; 1.37]1 Once-daily regimen + metformin ± DPP-IV inhibitor2 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needingthird party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table 4 Results from open-label clinical trials in type 2 diabetes mellitus: left - prior basalinsulin users, right - insulin naïve52 weeks of treatment 26 weeks of treatment

Tresiba1 Insulin Tresiba2 Sitagliptin2glargine(100 units/mL)1

N 744 248 225 222

HbA1c (%)

End of trial 7.1 7.1 7.2 7.7

Mean change -1.17 -1.29 -1.56 -1.22

Difference: 0.08 [-0.05; 0.21] Difference: -0.43 [-0.61; -0.24]

FPG (mmol/L)

End of trial 6.8 7.1 6.2 8.5

Mean change -2.44 -2.14 -3.22 -1.39

Difference: -0.29 [-0.65; 0.06] Difference: -2.17 [-2.59; -1.74]

Rate of hypoglycaemia (per patient year of exposure)

Severe hypoglycaemia 0.06 0.05 0.01 0

Confirmed3 11.09 13.63 3.07 1.26

Ratio: 0.82 [0.69; 0.99] Ratio: 3.81 [2.40; 6.05]

Nocturnal confirmed3 1.39 1.84 0.52 0.30

Ratio: 0.75 [0.58; 0.99] Ratio: 1.93 [0.90; 4.10]1 Once-daily regimen + insulin aspart to cover mealtime insulin requirements ± metformin ± pioglitazone2 Once-daily regimen ± metformin SU/glinide ± pioglitazone3 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needingthird party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table 5 Results from an open-label clinical trial with flexible dosing of Tresiba in type 2 diabetesmellitus26 weeks of treatment

Tresiba1 Tresiba Flex2 Insulin glargine(100 units/mL)3

N 228 229 230

HbA1c (%)

End of trial 7.3 7.2 7.1

Mean change -1.07 -1.28 -1.26

Difference: -0.13 [-0.29; 0.03]5 Difference: 0.04 [-0.12; 0.20]

FPG (mmol/L)

End of trial 5.8 5.8 6.2

Mean change from -2.91 -3.15 -2.78baseline

Difference: -0.05 [-0.45; 0.35]5 Difference: -0.42 [-0.82; -0.02]

Rate of hypoglycaemia (per patient year of exposure)

Severe 0.02 0.02 0.02

Confirmed4 3.63 3.64 3.48

Ratio: 1.10 [0.79; 1.52]6 Ratio: 1.03 [0.75; 1.40]

Nocturnal confirmed4 0.56 0.63 0.75

Ratio: 1.18 [0.66; 2.12]6 Ratio: 0.77 [0.44; 1.35]1 Once-daily regimen (with main evening meal) + one or two of the following oral antidiabetes agents: SU, metformin or

DPP-4 inhibitor2 Flexible once-daily regimen (intervals of approximately 8-40 hours between doses) + one or two of the following oralantidiabetes agents SU, metformin or DPP-4 inhibitor3 Once-daily regimen + one or two of the following oral antidiabetes agents: SU, metformin or DPP-4 inhibitor4 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needingthird party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.5 The difference is for Tresiba Flex - Tresiba6 The ratio is for Tresiba Flex/Tresiba.

In a 104-week clinical trial, 57% of patients with type 2 diabetes treated with Tresiba (insulindegludec) in combination with metformin achieved a target HbA1c <7.0%, and the remaining patientscontinued in a 26-week open-label trial and were randomised to add liraglutide or a single dose ofinsulin aspart (with the largest meal). In the insulin degludec + liraglutide arm, the insulin dose wasreduced by 20% in order to minimise the risk of hypoglycaemia. Addition of liraglutide resulted in astatistically significantly greater reduction of HbA1c (-0.73% for liraglutide vs -0.40% for comparator,estimated means) and body weight (-3.03 vs 0.72 kg, estimated means). The rate of hypoglycaemicepisodes (per patient year of exposure) was statistically significantly lower when adding liraglutidecompared to adding a single dose of insulin aspart (1.0 vs 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21).

Furthermore, two 64-week controlled, double-blind, randomised, cross-over, treat-to-target trials wereconducted in patients with at least one risk factor for hypoglycaemia and with type 1 diabetes mellitus(501 patients) or type 2 diabetes mellitus (721 patients). Patients were randomised to either Tresiba orinsulin glargine (100 units/mL) followed by cross-over. The trials evaluated the rate of hypoglycaemiaupon treatment with Tresiba compared to insulin glargine (100 units/mL) (see Table 6).

Table 6 Results from the double-blind, cross-over clinical trials in type 1 and type 2 diabetesmellitus

Type 1 diabetes mellitus Type 2 diabetes mellitus1 Insulin glargine 2 Insulin glargine

Tresiba 1 Tresiba(100 units/mL) (100 units/mL)2

N 501 721

HbA1c (%)

Baseline 7.6 7.6

End of treatment 6.9 6.9 7.1 7.0

FPG (mmol/L)

Baseline 9.4 7.6

End of treatment 7.5 8.4 6.0 6.1

Rate of severe hypoglycaemia30.69 0.92 0.05 0.09

Maintenance period4

Ratio: 0.65 [0.48; 0.89] Ratio: 0.54 [0.21; 1.42]

Rate of severe or BG confirmed symptomatic hypoglycaemia3,54 22.01 24.63 1.86 2.65

Maintenance period

Ratio: 0.89 [0.85; 0.94] Ratio: 0.70 [0.61; 0.80]

Rate of severe or BG confirmed symptomatic nocturnal hypoglycaemia3.52.77 4.29 0.55 0.94

Maintenance period4

Ratio: 0.64 [0.56; 0.73] Ratio: 0.58 [0.46; 0.74]1 In a once-daily regimen + insulin aspart to cover mealtime insulin requirements2 In a once-daily regimen ± OADs (any combination of metformin, dipeptidyl peptidase-4 inhibitor, alpha-glucosidaseinhibitor, thiazolidinediones, and sodium glucose cotransporter-2 inhibitor)3 Per patient year of exposure4 Episodes from week 16 in each treatment period5 Blood glucose (BG) confirmed symptomatic hypoglycaemia was defined as episodes confirmed by a plasma glucose valueof less than 3.1 mmol/L, with symptoms consistent with hypoglycaemia. Nocturnal confirmed hypoglycaemia was defined asepisodes between midnight and 6 a.m.

DEVOTE was a randomised, double-blind, and event-driven clinical trial with a median duration of 2years comparing the cardiovascular safety of Tresiba versus insulin glargine (100 units/mL) in 7,637patients with type 2 diabetes mellitus at high risk of cardiovascular events.

The primary analysis was time from randomisation to first occurrence of a 3-component major adversecardiovascular event (MACE) defined as cardiovascular death, non-fatal myocardial infarction, ornon-fatal stroke. The trial was designed as a non-inferiority trial to exclude a pre-specified risk marginof 1.3 for the hazard ratio (HR) of MACE comparing Tresiba to insulin glargine. The cardiovascularsafety of Tresiba as compared to insulin glargine was confirmed (HR 0.91 [0.78; 1.06]) (Figure 2).

Results from subgroup analyses (e.g. sex, diabetes duration, CV risk group and previous insulinregimen) was aligned with the primary analysis.

Hazard Ratio Insulin degludec Insulin glargine(95% CI) N (%) N (%)

Primary analysis (3-point MACE) 0.91 (0.78-1.06) 325 (8.51) 356 (9.32)

CV Death 0.96 (0.76-1.21) 136 (3.56) 142 (3.72)

Non-fatal Stroke 0.90 (0.65-1.23) 71 (1.86) 79 (2.07)

Non-fatal MI 0.85 (0.68-1.06) 144 (3.77) 169 (4.43)

All cause death 0.91 (0.75-1.11) 202 (5.29) 221 (5.79)0.7 0.9 1 1.1 1.3

Favours Favoursinsulin degludec insulin glargine

N: Number of subjects with a first EAC confirmed event during trial. %: Percentage of subjects with a first EAC confirmed event relative tothe number of randomised subjects. EAC: Event adjudication committee. CV: Cardiovascular. MI: Myocardial infarction. CI: 95%confidence interval.

Figure 2 Forest plot of analysis of the composite 3-point MACE and individual cardiovascularendpoints in DEVOTE

At baseline, HbA1c was 8.4% in both treatment groups and after 2 years HbA1c was 7.5% both with

Tresiba and insulin glargine.

Tresiba was superior compared to insulin glargine in terms of a lower rate of severe hypoglycaemicevents and a lower proportion of subjects experiencing severe hypoglycaemia. The rate of nocturnalsevere hypoglycaemia was significantly lower for Tresiba compared to insulin glargine (Table 7).

Table 7 Results from DEVOTE

Tresiba1 Insulin glargine(100 units/mL)1

N 3,818 3,819

Rate of hypoglycaemia (per 100 patient years of observation)

Severe 3.70 6.25

Rate ratio: 0.60 [0.48; 0.76]

Nocturnal severe2 0.65 1.40

Rate ratio: 0.47 [0.31; 0.73]

Proportions of patients with hypoglycaemia (percent of patients)

Severe 4.9 6.6

Odds ratio: 0.73 [0.60; 0.89]1 In addition to standard of care for diabetes and cardiovascular disease2 Nocturnal severe hypoglycaemia was defined as episodes between midnight and 6 a.m.

Tresiba has been studied in an open-label, randomised, active controlled clinical trial, in whichpregnant women with type 1 diabetes mellitus were treated within a basal-bolus treatment regimenwith Tresiba (92 women) or insulin detemir (96 women) as basal insulin, both in combination withinsulin aspart as meal time insulin (EXPECT).

Tresiba was non-inferior to insulin detemir as measured by HbA1c at last planned HbA1c visit prior todelivery after gestational week 16. Moreover, no difference between treatment groups was observedfor glycaemic control (change in HbA1c, FPG and PPG) during pregnancy.

No clinically relevant differences were observed between Tresiba and insulin detemir for the maternalsafety endpoints: hypoglycaemia, pre-term delivery and adverse events during the pregnancy. Pre-eclampsia was reported in 12 subjects treated with Tresiba (13.2%) and in 7 subjects (7.4%) who weretreated with insulin detemir. Non-planned caesarean section was reported in 23 subjects (25.3%)treated with Tresiba and in 15 subjects (16.0%) treated with insulin detemir. The majority of theadverse events reported in both groups were non-serious, mild in severity, unlikely related to the trialproduct and had the outcome “recovered/resolved”. No deaths were reported in the subjects who wererandomised in the trial.

No perinatal or neonatal death was reported. No clinically relevant differences were observed between

Tresiba and insulin detemir for the pregnancy endpoints (early foetal death, presence of majorabnormalities, neonatal hypoglycaemia, perinatal mortality, neonatal mortality, foetal macrosomia,large for gestational age, and adverse events in the infant during the 30 days after birth).

The European Medicines Agency has waived the obligation to submit the results of trials with Tresibain:

* Neonates and infants from birth to less than 12 months of age with type 1 diabetes mellitus andchildren from birth to less than 10 years of age with type 2 diabetes mellitus on the grounds thatthe disease or condition for which the specific medicinal product is intended does not occur inthe specified paediatric subset (see section 4.2 for information on paediatric use).

The efficacy and safety of Tresiba have been studied in a 1:1 randomised controlled clinical trial inchildren and adolescents with type 1 diabetes mellitus for a period of 26 weeks (n=350), followed by a26-week extension period (n=280). Patients in the Tresiba arm included 43 children aged 1-5 years,70 children aged 6-11 years and 61 adolescents aged 12-17 years. Tresiba dosed once daily showedsimilar reduction in HbA1c at week 52 and greater reduction in FPG from baseline versus thecomparator insulin detemir dosed once or twice daily. This was achieved with 30% lower daily dosesof Tresiba compared to insulin detemir. The rates (events per patient-year of exposure) of severehypoglycaemia (ISPAD definition; 0.51 vs 0.33), confirmed hypoglycaemia (57.71 vs 54.05) andnocturnal confirmed hypoglycaemia (6.03 vs 7.60) were comparable with Tresiba versus insulindetemir. In both treatment arms, children aged 6-11 years had a numerically higher rate of confirmedhypoglycaemia than in the other age groups. A numerically higher rate of severe hypoglycaemia inchildren aged 6-11 years in the Tresiba arm was observed. The rate of hyperglycaemic episodes withketosis was significantly lower for Tresiba versus insulin detemir, 0.68 and 1.09, respectively. Nosafety issues were identified with Tresiba with respect to adverse events and standard safetyparameters. Antibody development was sparse and had no clinical impact. Efficacy and safety data foradolescent patients with type 2 diabetes mellitus have been extrapolated from data for adolescent andadult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Resultssupport the use of Tresiba in adolescent patients with type 2 diabetes mellitus.

After subcutaneous injection, soluble and stable multi-hexamers are formed creating a depot of insulinin the subcutaneous tissue. Insulin degludec monomers gradually separate from the multi-hexamersthus resulting in a slow and continuous delivery of insulin degludec into the circulation.

Steady-state serum concentration is reached after 2-3 days of daily Tresiba administration.

During a period of 24 hours with once-daily treatment, the exposure of insulin degludec was evenlydistributed between the first and second 12 hours. The ratio between AUCIDeg,0-12h,SS and AUCIDeg,τ,SSwas 0.5.

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% inhuman plasma.

Degradation of insulin degludec is similar to that of human insulin; all metabolites formed areinactive.

The half-life after subcutaneous administration of Tresiba is determined by the rate of absorption fromthe subcutaneous tissue. The half-life of Tresiba is approximately 25 hours independent of dose.

Dose proportionality in total exposure is observed after subcutaneous administration within thetherapeutic dose range. In direct comparison, requirements for bioequivalence are met for Tresiba100 units/mL and Tresiba 200 units/mL (based on AUCIDeg,τ,SS and Cmax,IDeg,SS).

There is no gender difference in the pharmacokinetic properties of this medicinal product.

Elderly, race, renal and hepatic impairment

There is no difference in the pharmacokinetics of insulin degludec between elderly and younger adultpatients, between races or between healthy subjects and patients with renal or hepatic impairment.

Pharmacokinetic properties of insulin degludec in children (1-11 years) and adolescents (12-18 years)were at steady state comparable to those observed in adults with type 1 diabetes mellitus. Totalexposure after a single dose was, however, higher in children and adolescents than in adults with type1 diabetes mellitus.

Non-clinical data reveal no safety concerns for humans based on studies of safety pharmacology,repeated dose toxicity, carcinogenic potential, and toxicity to reproduction.

The ratio of mitogenic relative to metabolic potency for insulin degludec is comparable to that ofhuman insulin.

Glycerol

Metacresol

Phenol

Zinc acetate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

This medicinal product must not be mixed with any other medicinal products.

Substances added to Tresiba may cause degradation of insulin degludec.

Tresiba must not be added to infusion fluids.

30 months.

Tresiba 100 units/mL solution for injection in pre-filled pen

After first opening or carried as a spare, the medicinal product may be stored for a maximum of8 weeks. Do not store above 30°C. Can be stored in a refrigerator (2°C - 8°C). Keep the cap on thepen in order to protect from light.

Tresiba 200 units/mL solution for injection in pre-filled pen

After first opening or carried as a spare, the medicinal product may be stored for a maximum of8 weeks. Do not store above 30°C. Can be stored in a refrigerator (2°C - 8°C). Keep the cap on thepen in order to protect from light.

Tresiba 100 units/mL solution for injection in cartridge

After first opening or carried as a spare, the medicinal product may be stored for a maximum of8 weeks. Do not store above 30°C. Do not refrigerate. Keep cartridges in the outer carton in order toprotect from light.

Tresiba 100 units/mL solution for injection in pre-filled pen

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep away from the freezing element.

Keep the cap on the pen in order to protect it from light.

Tresiba 200 units/mL solution for injection in pre-filled pen

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep away from the freezing element.

Keep the cap on the pen in order to protect it from light.

Tresiba 100 units/mL solution for injection in cartridge

Store in a refrigerator (2°C - 8°C). Do not freeze.

Keep away from the freezing element.

Keep cartridges in the outer carton in order to protect them from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Tresiba 100 units/mL solution for injection in pre-filled pen3 mL solution in a cartridge (type 1 glass) with a plunger (halobutyl) and a laminate rubber sheet(halobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 5 (without needles) and multipack containing 10 (2 packs of5) (without needles) pre-filled pens.

Not all pack sizes may be marketed.

Tresiba 200 units/mL solution for injection in pre-filled pen3 mL solution in a cartridge (type 1 glass) with a plunger (halobutyl) and a laminate rubber sheet(halobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene.

Pack sizes of 1 (with or without needles), 2 (without needles), 3 (without needles), 5 (without needles)and multipack containing 6 (2 packs of 3) (without needles) pre-filled pens.

Not all pack sizes may be marketed.

Tresiba 100 units/mL solution for injection in cartridge3 mL solution in a cartridge (type 1 glass) with a plunger (halobutyl) and a laminate rubber sheet(halobutyl/polyisoprene) in a carton.

Pack sizes of 5 and 10 cartridges.

Not all pack sizes may be marketed.

This medicinal product is for use by one person only. It must not be refilled.

Tresiba must not be used if the solution does not appear clear and colourless.

Tresiba which has been frozen must not be used.

A new needle must always be attached before each use. Needles must not be re-used. The patientshould discard the needle after each injection.

In the event of blocked needles, patients must follow the instructions described in the instructions foruse accompanying the package leaflet.

Any waste material should be disposed of in accordance with local requirements.

For detailed instructions for use, see the package leaflet.

Tresiba in a pre-filled pen is available in two strengths. “Tresiba 100 units/mL” or “Tresiba200 units/mL” is clearly marked on the pen label and packaging.

Tresiba 100 units/mL solution for injection in pre-filled pen

Tresiba 100 units/mL packaging and label are light green.

The pre-filled pen (FlexTouch) is designed to be used with NovoFine/NovoTwist injection needles upto a length of 8 mm. It delivers 1-80 units in steps of 1 unit. Detailed instructions accompanying thepre-filled pen must be followed.

Tresiba 200 units/mL solution for injection in pre-filled pen

Tresiba 200 units/mL packaging and label are dark green with striping with a red box highlighting theformulation strength.

The pre-filled pen (FlexTouch) is designed to be used with NovoFine/NovoTwist injection needles upto a length of 8 mm. It delivers 2-160 units in steps of 2 units. Detailed instructions accompanying thepre-filled pen must be followed.

Tresiba 100 units/mL solution for injection in cartridge

The cartridge (Penfill) is designed to be used with Novo Nordisk delivery systems (durable devices forrepeated use not included in the pack) and NovoFine/NovoTwist injection needles up to a length of8 mm. Detailed instructions accompanying the delivery system must be followed.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

Tresiba 100 units/mL solution for injection in pre-filled pen

EU/1/12/807/001

EU/1/12/807/002

EU/1/12/807/003

EU/1/12/807/004

EU/1/12/807/005

Tresiba 200 units/mL solution for injection in pre-filled pen

EU/1/12/807/009

EU/1/12/807/006

EU/1/12/807/010

EU/1/12/807/012

EU/1/12/807/013

EU/1/12/807/015

EU/1/12/807/016

Tresiba 100 units/mL solution for injection in cartridge

EU/1/12/807/007

EU/1/12/807/008

Date of first authorisation: 21 January 2013

Date of latest renewal: 21 September 2017

Detailed information on this medicinal product is available on the web site of the European Medicines

Agency http://www.ema.europa.eu