RYZODEG 100U / ml (2.56mg+1.05mg) injection for pre-filled pen medication leaflet

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

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

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

1 mL solution contains 100 units insulin degludec/insulin aspart* in the ratio 70/30 (equivalent to2.56 mg insulin degludec and 1.05 mg insulin aspart).

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

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

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

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

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

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

*Produced in Saccharomyces cerevisiae by recombinant DNA technology.

For the full list of excipients, see section 6.1.

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

Solution for injection .

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

Solution for injection.

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

Solution for injection.

Clear, colourless, neutral solution.

Treatment of diabetes mellitus in adults, adolescents and children from the age of 2 years.

This medicinal product is a soluble insulin product consisting of the basal insulin degludec and therapid-acting prandial insulin aspart.

The potency of insulin analogues, including Ryzodeg, is expressed in units. One (1) unit of this insulincorresponds to 1 international unit of human insulin, 1 unit of insulin glargine, 1 unit of insulindetemir or 1 unit of biphasic insulin aspart.

Ryzodeg is to be dosed in accordance with the individual patient’s needs. Dose-adjustments arerecommended to be based on fasting plasma glucose measurements.

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

Ryzodeg can be administered once or twice daily with the main meal(s) alone, in combination withoral antidiabetic medicinal products, and in combination with bolus insulin (see section 5.1). Whenusing Ryzodeg once-daily, changing to twice daily should be considered when higher doses areneeded, e.g. to avoid hypoglycaemia. Split the dose based on individual patient’s needs and administerwith main meals.

Patients with type 1 diabetes mellitus

Ryzodeg can be administered once daily at mealtime in combination with short-/rapid-acting insulin atthe remaining meals.

Flexibility in dosing time

Ryzodeg allows for flexibility in the timing of insulin administration as long as it is dosed with themain meal(s).

If a dose of this medicinal product is missed, the patient can take the missed dose with the next mainmeal of that day and thereafter resume the usual dosing schedule. Patients should not take an extradose to make up for a missed dose.

The recommended total daily starting dose is 10 units with meal(s) followed by individual dosageadjustments.

Patients with type 1 diabetes mellitus

The recommended starting dose of Ryzodeg is 60-70% of the total daily insulin requirements.

This medicinal product is to be used once daily at mealtime in combination with short-/rapid-actinginsulin at the remaining meals followed by individual dosage adjustments.

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.

Patients switching from once-daily basal or premix insulin therapy can be converted unit-to-unit toonce- or twice-daily Ryzodeg at the same total insulin dose as the patient’s previous total daily insulindose.

Patients switching from more than once-daily basal or premix insulin therapy can be convertedunit-to-unit to once- or twice-daily Ryzodeg at the same total insulin dose as the patient’s previoustotal daily insulin dose.

Patients switching from basal/bolus insulin therapy to Ryzodeg will need to convert their dose basedon individual needs. In general, patients are initiated on the same number of basal units.

Patients with type 1 diabetes mellitus

The recommended starting dose of Ryzodeg is 60-70% of the total daily insulin requirements incombination with short-/rapid-acting insulin at the remaining meals followed by individual dosageadjustments.

Elderly (≥ 65 years old)

Ryzodeg can be used in the elderly. Glucose monitoring is to be intensified and the insulin doseadjusted on an individual basis (see section 5.2).

Ryzodeg can be used in renal and hepatic impaired patients. Glucose monitoring is to be intensifiedand the 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 of2 years.

This medicinal product can be used in adolescents and children from the age of 2 years (see section5.1). When changing from another insulin regimen to Ryzodeg, dose reduction of total insulin needs tobe considered on an individual basis in order to minimise the risk of hypoglycaemia (see section 4.4).

Ryzodeg should be used with special caution in children 2 to 5 years old because data from the clinicaltrial indicate that there may be a higher risk for severe hypoglycaemia in children in this age group(see sections 4.4, pct. 4.8 and 5.1).

Subcutaneous use only.

This medicinal product must not be administered intravenously as it may result in severehypoglycaemia.

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.

This medicinal product must not be drawn from the cartridge of the pre-filled pen into a syringe (seesection 4.4).

Ryzodeg is administered subcutaneously by injection in the abdominal wall, the upper arm or thethigh. 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).

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

Ryzodeg comes in a pre-filled pen designed to be used with NovoFine or NovoTwist injection needles.

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

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

Ryzodeg comes in a pre-filled pen designed to be used with NovoFine or NovoTwist injection needles.

The pre-filled pen delivers 1-60 units in steps of 1 unit.

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

Ryzodeg comes in a cartridge designed to be used with Novo Nordisk insulin delivery systems and

NovoFine or NovoTwist injection needles.

Hypersensitivity to the active substances 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, extra care should be taken to match insulin doses with food intake and physical activitiesin order to minimise the risk of hypoglycaemia. Ryzodeg may be associated with higher occurrence ofsevere hypoglycaemia compared to a basal-bolus regimen in the paediatric population, particularly inchildren 2 to 5 years old (see section 5.1). For this age group, Ryzodeg should be considered on anindividual basis.

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 or insulin products with a basal component, the prolonged effectof Ryzodeg may delay recovery from hypoglycaemia.

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.

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.

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.

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 Ryzodeg 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 accidental mix-ups

Patients must be instructed to always check the insulin label before each injection to avoid accidentalmix-ups between Ryzodeg and 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.

There is no clinical experience with the use of this medicinal product in pregnant women.

Animal reproduction studies have not revealed any difference between insulin degludec and humaninsulin regarding embryotoxicity and teratogenicity.

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.

There is no clinical experience with Ryzodeg 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/insulin aspart is excreted in human milk. No metabolic effectsare anticipated 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 Not known Lipodystrophy

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 Ryzodeg, 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

Ryzodeg. These reactions are usually mild and transitory and they normally disappear duringcontinued treatment.

Ryzodeg 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 trialin children aged 2 to less than 18 years. The frequency, type and severity of adverse reactions in thepaediatric population do not indicate differences to the experience in the general diabetes populationwith the exception of a signal of higher occurrence of severe hypoglycaemia compared to a basal-bolus regimen in the paediatric population, particularly in children 2 to 5 years old (see section 4.2, pct. 4.4and 5.1).

Based on results from clinical trials, the frequency, type and severity of adverse reactions observed inthe elderly and in patients with renal or hepatic impairment do not indicate any differences to thebroader experience 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 or with glucose given intravenously by a healthcare professional. Glucose mustbe given intravenously if the patient does not respond to glucagon within 10 to 15 minutes.

Upon regaining consciousness, administration of oral carbohydrates is recommended for thepatient in order to prevent a relapse.

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, intermediate-or long-acting combined with fast-acting, ATC code: A10AD06.

Insulin degludec and insulin aspart bind specifically to the human insulin receptor and result in thesame pharmacological 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.

The pharmacodynamic effect of Ryzodeg is distinctively separated for the two components (Figure 1),and the resulting action profile reflects the individual components, the rapid-acting insulin aspart andthe basal component insulin degludec.

The basal component of Ryzodeg (insulin degludec) forms soluble multi-hexamers upon subcutaneousinjection, resulting in a depot from which insulin degludec is continuously and slowly absorbed intothe circulation leading to a flat and stable glucose-lowering effect. This effect is maintained in theco-formulation with insulin aspart and does not interfere with the rapid-acting insulin aspartmonomers.

Ryzodeg has a rapid onset of action occurring soon after injection providing mealtime coverage whilethe basal component has a flat and stable action profile providing continuous coverage of the basalinsulin requirements. The duration of action of a single-dose of Ryzodeg is beyond 24 hours.

Time since injection (hours)

Treatment IDegAsp 0.8 U/kg

Figure 1: Pharmacodynamics, single dose - Mean glucose infusion rate profile - Patients withtype 1 diabetes - 0.8 U/kg Ryzodeg - Trial 3539

The total and maximum glucose-lowering effects of Ryzodeg increase linearly with increasing doses.

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

There is no difference in the pharmacodynamic effect of this medicinal product between elderly andyounger patients.

Glucose Infusion Rate (mg/(kg*min))

Seven multinational, randomised, controlled, open-label, treat-to-target clinical studies of between 26and 52 weeks’ duration were conducted exposing a total of 1,761 patients with diabetes mellitus (1study involving 362 patients in type 1 diabetes mellitus and 6 studies involving 1,399 patients in type2 diabetes mellitus) to Ryzodeg. Ryzodeg administered once daily o.d. was compared to insulinglargine (100 units/mL) (IGlar) o.d. in two trials in type 2 diabetes mellitus (Table 1). Ryzodeg b.i.d.was compared to biphasic insulin aspart 30 (BIAsp 30) b.i.d. in two trials in type 2 diabetes mellitus(Table 2) and to insulin degludec (IDeg) o.d. plus insulin aspart (IAsp) 2-4 times daily in one trial intype 2 diabetes mellitus. In one trial in type 2 diabetes mellitus Ryzodeg o.d. was compared to insulinglargine (IGlar) o.d. plus IAsp o.d. After 26 weeks of treatment the Ryzodeg dose could be split intob.i.d. In all trials in type 2 diabetes mellitus, oral antidiabetic drugs (OADs) were allowed. Ryzodego.d. plus insulin aspart (IAsp) was also compared to o.d. or b.i.d. insulin detemir (IDet) plus IAsp intype 1 diabetes mellitus (Table 3).

Non-inferiority in HbA1c change from baseline to end-of-trial was confirmed in 6 of the 7 studiesagainst all comparators when treating patients to target, whereas non-inferiority was not confirmed inone study (comparing IDegAsp b.i.d. with IDeg o.d. plus IAsp 2-4 times daily) in type 2 diabetesmellitus.

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

In two trials combining insulin and OAD treatment in both insulin-naïve (insulin initiation) andinsulin-using (insulin intensification) patients with type 2 diabetes mellitus, Ryzodeg o.d.demonstrated similar glycaemic control (HbA1c) compared to IGlar (administered according to label)(Table 1). As Ryzodeg contains a rapid-acting mealtime insulin (insulin aspart), prandial glycaemiccontrol at the dosing meal is improved relative to administering basal insulin only; see trial results in

Table 1. A lower rate of nocturnal hypoglycaemia (defined as episodes between midnight and 6 a.m.confirmed by plasma glucose < 3.1 mmol/L or by patient needing third party assistance) was observedwith Ryzodeg relative to IGlar (Table 1).

Ryzodeg b.i.d. demonstrated similar glycaemic control (HbA1c) compared with BIAsp 30 b.i.d. inpatients with type 2 diabetes mellitus. It demonstrates superior improvements in fasting plasmaglucose levels compared to patients treated with BIAsp 30. Ryzodeg causes a lower rate of overall andnocturnal hypoglycaemia (Table 2).

Ryzodeg b.i.d. was compared with IDeg o.d. plus IAsp (2-4 daily injections) in patients with type 2diabetes mellitus treated with basal insulin in need of treatment intensification with mealtime insulin.

The study design included a standardised treatment schedule but allowed for certain adjustments tomeet individual needs. Both treatments improved glycaemic control with an estimated mean reductionwith Ryzodeg (-1.23%) against IDeg plus IAsp (-1.42%) for the primary endpoint of change frombaseline in HbA1c at 26 weeks. This did not meet the pre-specified non-inferiority margin of 0.4%[0.18 (-0.04; 0.41)]. There were no statistically significant differences between the two treatmentgroups.

In one trial of patients with type 2 diabetes mellitus treated with basal insulin, in need of treatmentintensification with mealtime insulin, Ryzodeg o.d. was compared to IGlar o.d. plus IAsp o.d. over26 weeks. After 26 weeks, the Ryzodeg dose could be split into b.i.d. dosing in the Ryzodeg arm andadditional IAsp doses could be administered at other meals (up to 3 times daily) in the IGlar arm. Thestudy design included a standardised treatment schedule but allowed for certain adjustments to meetindividual needs. Ryzodeg o.d. demonstrated similar glycaemic control (HbA1c) compared to IGlaro.d. plus IAsp o.d. after 26 weeks (the estimated mean reductions are -1.01% vs -1.09%). Ryzodego.d.or b.i.d demonstrated similar glycaemic control (HbA1c) compared to IGlar o.d. plus IAsp 1-3 times daily after 38 weeks (the estimated mean reductions are -1.17% vs -1.26%). Ryzodeg showeda lower rate of nocturnal hypoglycaemia compared to IGlar o.d. plus IAsp during 26 weeks (0.42 vs0.76 estimated rates per patient year of exposure) and 38 weeks (0.51 vs 0.83 estimated rates perpatient year of exposure).

Patients with type 1 diabetes mellitus

In patients with type 1 diabetes mellitus, treatment with Ryzodeg o.d. plus IAsp for the remainingmeals demonstrated similar glycaemic control (HbA1c and fasting plasma glucose) with a lower rate ofnocturnal hypoglycaemia compared to a basal/bolus regimen with IDet plus IAsp at all meals (Table3).

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

Table 1 Result from two 26-weeks’ trials in type 2 diabetes mellitus with Ryzodeg given oncedaily

Ryzodeg (o.d.)1 IGlar (o.d.)1 Ryzodeg (o.d.)2 I G lar (o.d.)2

Insulin naïve Insulin naïve Insulin users Insulin users

N 266 263 230 233

Mean HbA1c (%)

End of trial 7.2 7.2 7.3 7.4

Mean change -1.65 -1.72 -0.98 -1.00

Difference: 0.03 [-0.14;0.20] Difference: -0.03 [-0.20;0.14]

Fasting Plasma Glucose (FPG) (mmol/L)

End of trial 6.8 6.3 6.3 6.0

Mean change -3.32 -4.02 -1.68 -1.88

Difference: 0.51 [0.09;0.93] Difference: 0.33 [-0.11;0.77]

Prandial Blood glucose Increment 90 minutes after dosing meal (Plasma) (mmol/L)

End of trial 1.9 3.4 1.2 2.6

Mean change -1.5 -0.3 -1.5 -0.6

Hypoglycaemia Rate (per patient year of exposure)

Severe 0.01 0.01 0.00 0.04

Confirmed3 4.23 1.85 4.31 3.20

Ratio: 2.17 [1.59;2.94] Ratio: 1.43 [1.07;1.92]

Nocturnal 0.19 0.46 0.82 1.01confirmed3

Ratio: 0.29 [0.13;0.65] Ratio: 0.80 [0.49;1.30]1 Once-daily regimen + Metformin2 Once-daily regimen + Metformin ± pioglitazone ± DPP-4 inhibitor3 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 2 Result from two 26-weeks’ trials in type 2 diabetes mellitus with Ryzodeg given twicedaily

Ryzodeg (b.i.d.)1 BIAsp 30 Ryzodeg (b.i.d.)2 BIAsp 30

Insulin users (b.i.d.)1 Insulin users (b.i.d.)2

Insulin users Insulin users

N 224 222 280 142

Mean HbA1c (%)

End of trial 7.1 7.1 7.1 7.0

Mean change -1.28 -1.30 -1.38 -1.42

Difference: -0.03 [-0.18;0.13] Difference: 0.05 [-0.10;0.20]

FPG (mmol/L)

End of trial 5.8 6.8 5.4 6.5

Mean change -3.09 -1.76 -2.55 -1.47

Difference: -1.14 [-1.53;-0.76] Difference: -1.06 [-1.43;-0.70]

Hypoglycaemia Rate (per patient year of exposure)

Ryzodeg (b.i.d.)1 BIAsp 30 Ryzodeg (b.i.d.)2 BIAsp 30

Insulin users (b.i.d.)1 Insulin users (b.i.d.)2

Insulin users Insulin users

Severe 0.09 0.25 0.05 0.03

Confirmed 3 9.72 13.96 9.56 9.52

Ratio: 0.68 [0.52;0.89] Ratio: 1.00 [0.76;1.32]

Nocturnal confirmed3 0.74 2.53 1.11 1.55

Ratio: 0.27 [0.18;0.41] Ratio: 0.67 [0.43;1.06]1 Twice-daily regimen ± metformin ± pioglitazone ± DPP-4 inhibitor2 Twice-daily regimen ± metformin3 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 Result of a 26-weeks’ trial in type 1 diabetes mellitus with Ryzodeg given once daily

Ryzodeg (o.d.)1 IDet (o.d./b.i.d.)2

N 366 182

Mean HbA1c (%)

End of trial 7.6 7.6

Mean change -0.73 -0.68

Difference: -0.05 [-0.18;0.08]

FPG (mmol/L)

End of trial 8.7 8.6

Mean change -1.61 -2.41

Difference: 0.23 [-0.46;0.91]

Hypoglycaemia Rate (per patient year of exposure)

Severe 0.33 0.42

Confirmed3 39.2 44.3

Ratio: 0.91 [0.76;1.09]

Nocturnal confirmed3 3.71 5.72

Ratio: 0.63 [0.49;0.81]1 Once-daily regimen + insulin aspart to cover mealtime insulin requirements2 Once- or twice-daily regimen + insulin aspart to cover mealtime insulin requirements3 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.

DEVOTE was a randomised, double-blind, and event-driven clinical trial focusing on insulindegludec, the long-acting component of Ryzodeg. The trial had a median duration of 2 years andcompared the cardiovascular safety of insulin degludec vs 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 insulin degludec to insulin glargine. Thecardiovascular safety of insulin degludec 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) were aligned with the primary analysis. At baseline, HbA1c was 8.4% in both treatmentgroups and after 2 years HbA1c was 7.5% both with insulin degludec and insulin glargine.

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 (0.76-1.11) 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

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

Ryzodeg in:

* Neonates and infants from birth to less than 12 months of age with type 1 diabetes mellitus.

* In all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 forinformation on paediatric use).

The efficacy and safety of Ryzodeg have been studied in a randomised controlled clinical trial inchildren and adolescents with diabetes mellitus type 1 for a period of 16 weeks (n=362). Patients in the

Ryzodeg arm included 40 exposed children aged 2-5 years, 61 children aged 6-11 years and 80adolescents aged 12-17 years. Ryzodeg dosed once daily with the main meal plus insulin aspart for theremaining meals showed similar reduction in HbA1c at week 16 and no differences in FPG and SMPGcompared to comparator insulin detemir dosed once or twice daily plus mealtime insulin aspart. Atweek 16, the mean total daily insulin dose was 0.88 vs 1.01 units/kg in the Ryzodeg and insulindetemir arms, respectively. The rates (events per patient-year of exposure) of confirmedhypoglycaemia (ISPAD 2009 definition: 46.23 vs 49.55) and nocturnal confirmed hypoglycaemia(5.77 vs 5.40) were comparable with Ryzodeg vs insulin detemir whereas the rate of severehypoglycaemia (0.26 vs 0.07) was higher in the Ryzodeg arm although the difference was notstatistically significant. Few severe hypoglycaemic episodes were reported in each group; the observedrate of severe hypoglycaemia within the Ryzodeg arm was higher for subjects aged 2-5 yearscompared to subjects aged 6-11 years or 12-17 years (0.42 vs 0.21 and 0.21 respectively). An efficacyand safety evaluation for adolescent patients with type 2 diabetes mellitus has been made using datafrom adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetesmellitus. This assessment supports the use of Ryzodeg in adolescent patients with type 2 diabetesmellitus.

After subcutaneous injection, soluble and stable multi-hexamers of insulin degludec are formedcreating a depot of insulin in the subcutaneous tissue, while not interfering with the rapid release ofinsulin aspart monomers into the circulation. Insulin degludec monomers gradually separate from themulti-hexamers thus resulting in a slow and continuous delivery of insulin degludec into thecirculation. Steady-state serum concentration of the basal component (insulin degludec) is reachedafter 2-3 days of daily Ryzodeg administration.

The rapid absorption characteristics of the well-established insulin aspart are maintained by Ryzodeg.

The pharmacokinetic profile for insulin aspart appears 14 minutes after injection with a peakconcentration after 72 minutes.

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% inhuman plasma. Insulin aspart has a low binding to plasma proteins (<10%), similar to that seen withregular human insulin.

Degradation of insulin degludec and insulin aspart is similar to that of human insulin; all metabolitesformed are inactive.

The half-life after subcutaneous administration of Ryzodeg is determined by the rate of absorptionfrom the subcutaneous tissue. The half-life of the basal component (insulin degludec) at steady state is25 hours independent of dose.

Total exposure with Ryzodeg increases proportionally with increasing dose of the basal component(insulin degludec) and the mealtime component (insulin aspart) in type 1 and type 2 diabetes mellitus.

There is no gender difference in the pharmacokinetic properties of Ryzodeg.

Elderly, race, renal and hepatic impairment

There are no clinically relevant differences in the pharmacokinetics of Ryzodeg between elderly andyounger adult patients, between races or between healthy subjects and patients with renal or hepaticimpairment.

The pharmacokinetic properties of Ryzodeg in type 1 diabetes mellitus were investigated in children(6-11 years) and adolescents (12-18 years) and compared to adults after single dose administration.

The steady-state pharmacokinetic properties of the insulin degludec component of Ryzodeg wereinvestigated using a population pharmacokinetic analysis in children down to 1 year of age.

Total exposure and peak concentration of insulin aspart were higher in children than in adults andwere similar for adolescents and adults.

The 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.

Total exposure of insulin degludec after single dose administration was, however, higher in childrenand adolescents than in adults with type 1 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

Sodium chloride

Zinc acetate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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

Substances added to Ryzodeg may cause degradation of insulin degludec and/or insulin aspart.

Ryzodeg must not be added to infusion fluids.

30 months.

Ryzodeg 100 units/mL FlexTouch/FlexPen solution for injection in pre-filled pen

After first opening or carried as a spare, the medicinal product may be stored for a maximum of4 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.

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

After first opening or carried as a spare, the medicinal product may be stored for a maximum of4 weeks. Do not store above 30°C. Do not refrigerate. Keep the cartridges in the outer carton in orderto protect from light.

Ryzodeg 100 units/mL FlexTouch/FlexPen 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 from light.

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

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

Keep away from the freezing element.

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

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

Ryzodeg 100 units/mL FlexTouch 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 multidose disposable pre-filled 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.

Ryzodeg 100 units/mL FlexPen 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 multidose disposable pre-filled pen made of polypropylene.

Pack size of 5 pre-filled pens.

Ryzodeg 100 units/mL Penfill 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.

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

Ryzodeg 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.

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

The pre-filled pen is designed to be used with NovoFine/NovoTwist injection needles up to a length of8 mm. It delivers 1-80 units in steps of 1 unit. Detailed instructions accompanying the pre-filled penmust be followed.

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

The pre-filled pen is designed to be used with NovoFine/NovoTwist injection needles up to a length of8 mm. It delivers 1-60 units in steps of 1 unit. Detailed instructions accompanying the pre-filled penmust be followed.

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

The cartridge is designed to be used with Novo Nordisk delivery systems (durable devices for repeateduse not included in the pack) and NovoFine/NovoTwist injection needles up to a length of 8 mm.

Detailed instructions accompanying the delivery system must be followed.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

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

EU/1/12/806/001

EU/1/12/806/002

EU/1/12/806/003

EU/1/12/806/004

EU/1/12/806/005

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

EU/1/12/806/009

Ryzodeg 100 units/mL Penfill solution for injection in cartridge

EU/1/12/806/007

EU/1/12/806/008

Date of first authorisation: 21 January 2013

Date of latest renewal: 21 September 2017

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

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