XULTOPHY 100U / 3.6mg / ml solution for injection in pre-filled pen medication leaflet

Xultophy 100 units/mL + 3.6 mg/mL solution for injection.

1 mL solution contains 100 units insulin degludec* and 3.6 mg liraglutide*.

*Produced in Saccharomyces cerevisiae by recombinant DNA technology.

One pre-filled pen contains 3 mL equivalent to 300 units insulin degludec and 10.8 mg liraglutide.

One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless, isotonic solution.

Xultophy is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitusto improve glycaemic control as an adjunct to diet and exercise in addition to other oral medicinalproducts for the treatment of diabetes. For study results with respect to combinations, effects onglycaemic control, and the populations studied, see sections 4.4, 4.5 and 5.1.

Xultophy is given once daily by subcutaneous administration. Xultophy can be administered at anytime of the day, preferably at the same time of the day.

Xultophy is to be dosed in accordance with the individual patient’s needs. It is recommended tooptimise glycaemic 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.

Patients who forget a dose are advised to take it upon discovery and then resume their usual once-dailydosing schedule. A minimum of 8 hours between injections should always be ensured. This alsoapplies when administration at the same time of the day is not possible.

Xultophy is administered as dose steps. One dose step contains 1 unit of insulin degludec and0.036 mg of liraglutide. The pre-filled pen can provide from 1 up to 50 dose steps in one injection inincrements of one dose step. The maximum daily dose of Xultophy is 50 dose steps (50 units insulindegludec and 1.8 mg liraglutide). The dose counter on the pen shows the number of dose steps.

Add-on to oral glucose-lowering medicinal products

The recommended starting dose of Xultophy is 10 dose steps (10 units insulin degludec and 0.36 mgliraglutide).

Xultophy can be added to existing oral antidiabetic treatment. When Xultophy is added to sulfonylureatherapy, a reduction in the dose of sulfonylurea should be considered (see section 4.4).

Transfer from GLP-1 receptor agonist

Therapy with GLP-1 receptor agonists should be discontinued prior to initiation of Xultophy. Whentransferring from a GLP-1 receptor agonist, the recommended starting dose of Xultophy is 16 dosesteps (16 units insulin degludec and 0.6 mg liraglutide) (see section 5.1). The recommended startingdose should not be exceeded. If transferring from a long-acting GLP-1 receptor agonist (e.g. once-weekly dosing), the prolonged action should be considered. Treatment with Xultophy should beinitiated at the moment the next dose of the long-acting GLP-1 receptor agonist would have beentaken. Close glucose monitoring is recommended during the transfer and in the following weeks.

Transfer from any insulin regimen that includes a basal insulin component

Therapy with other insulin regimens should be discontinued prior to initiation of Xultophy. Whentransferring from any other insulin therapy that includes a basal insulin component, the recommendedstarting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide) (seesection 4.4 and 5.1). The recommended starting dose should not be exceeded, but may be reduced toavoid hypoglycaemia in selected cases. Close glucose monitoring is recommended during the transferand in the following weeks.

Elderly patients (≥65 years old)

Xultophy can be used in elderly patients. Glucose monitoring is to be intensified and the dose adjustedon an individual basis.

When Xultophy is used in patients with mild, moderate or severe renal impairment, glucosemonitoring is to be intensified and the dose adjusted on an individual basis. Xultophy cannot berecommended for use in patients with end-stage renal disease (see sections 5.1 and 5.2).

Xultophy can be used in patients with mild or moderate hepatic impairment. Glucose monitoring is tobe intensified and the dose adjusted on an individual basis.

Due to the liraglutide component, Xultophy is not recommended for use in patients with severe hepaticimpairment (see section 5.2).

There is no relevant use of Xultophy in the paediatric population.

Xultophy is for subcutaneous use only. Xultophy must not be administered intravenously orintramuscularly.

Xultophy is administered subcutaneously by injection in the thigh, the upper arm or the abdomen.

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). For further instructions onadministration, see section 6.6.

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

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).

Hypersensitivity to either or both active substances or to any of the excipients listed in section 6.1.

Xultophy should not be used in patients with type 1 diabetes mellitus or for the treatment of diabeticketoacidosis.

Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal orunplanned strenuous physical exercise may lead to hypoglycaemia. In combination with sulfonylurea,the risk of hypoglycaemia may be lowered by a reduction in the dose of sulfonylurea. Concomitantdiseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may requirechanges of the Xultophy dose. Patients whose blood glucose control is greatly improved (e.g. byintensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia andmust be advised accordingly. Usual warning symptoms (see section 4.8) of hypoglycaemia maydisappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delayrecovery from hypoglycaemia.

Inadequate dosing and/or discontinuation of antidiabetic treatment may lead to hyperglycaemia andpotentially to hyperosmolar coma. In case of discontinuation of Xultophy, ensure that instruction forinitiation of alternative antidiabetic treatment is followed. Furthermore, concomitant illness, especiallyinfections, may lead to hyperglycaemia and thereby cause an increased requirement for antidiabetictreatment. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours ordays. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dryskin, dry mouth, and loss of appetite as well as acetone odour of breath.

Administration of rapid-acting insulin should be considered in situations of severe hyperglycaemia.

Untreated hyperglycaemic events eventually lead to hyperosmolar coma/diabetic ketoacidosis, whichis 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.

Combination of pioglitazone and insulin medicinal products

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulinmedicinal products, especially in patients with risk factors for development of cardiac failure. Thisshould be kept in mind if treatment with the combination of pioglitazone and Xultophy is considered.

If the combination is used, patients should be observed for signs and symptoms of heart failure, weightgain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptomsoccurs.

Eye disorder

Intensification of therapy with insulin, a component of Xultophy, with abrupt improvement inglycaemic control may be associated with temporary worsening of diabetic retinopathy, while long-term improved glycaemic control decreases the risk of progression of diabetic retinopathy.

Antibody formation

Administration of Xultophy may cause formation of antibodies against insulin degludec and/orliraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the Xultophydose in order to correct a tendency to hyper- or hypoglycaemia. Very few patients developed insulindegludec specific antibodies, antibodies cross-reacting to human insulin or anti-liraglutide antibodiesfollowing treatment with Xultophy. Antibody formation has not been associated with reduced efficacyof Xultophy.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, including liraglutide.

Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis issuspected, Xultophy should be discontinued; if acute pancreatitis is confirmed, Xultophy should not berestarted.

Thyroid adverse events

Thyroid adverse events, such as goitre have been reported in clinical trials with GLP-1 receptoragonists including liraglutide, and in particular in patients with pre-existing thyroid disease. Xultophyshould therefore be used with caution in these patients.

Inflammatory bowel disease and diabetic gastroparesis

There is no experience with Xultophy in patients with inflammatory bowel disease and diabeticgastroparesis. Xultophy is therefore not recommended in these patients.

Signs and symptoms of dehydration, including renal impairment and acute renal failure have beenreported in clinical trials with GLP-1 receptor agonists including liraglutide, a component of Xultophy.

Patients treated with Xultophy should be advised of the potential risk of dehydration in relation togastrointestinal side effects and take precautions to avoid fluid depletion.

Avoidance of medication errors

Patients must be instructed to always check the pen label before each injection to avoid accidentalmix-ups between Xultophy and other injectable diabetes medicinal 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 use asyringe 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).

Transfer to Xultophy from doses of basal insulin <20 and >50 units has not been studied.

There is no therapeutic experience in patients with congestive heart failure New York Heart

Association (NYHA) class IV and Xultophy is therefore not recommended for use in these patients.

Xultophy contains less than 1 mmol sodium (23 mg) per dose, therefore the medicinal product isessentially ‘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.

Interaction studies with Xultophy have not been performed.

A number of substances affect glucose metabolism and may require dose adjustment of Xultophy.

The following substances may reduce the Xultophy requirement:

Antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensinconverting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides.

The following substances may increase the Xultophy requirement:

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

Beta-blockers may mask the symptoms of hypoglycaemia.

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

Alcohol may intensify or reduce the hypoglycaemic effect of Xultophy.

In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interactionand protein binding is low for both liraglutide and insulin degludec.

The small delay of gastric emptying with liraglutide may influence absorption of concomitantlyadministered oral medicinal products. Interaction studies did not show any clinically relevant delay ofabsorption.

No interaction study has been performed. A clinically relevant interaction with active substances withpoor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiationof Xultophy treatment in patients on warfarin or other coumarin derivatives more frequent monitoringof INR (International Normalised Ratio) is recommended.

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1,000 mg.

Paracetamol Cmax was decreased by 31% and median tmax was delayed up to 15 min. No doseadjustment for concomitant use of paracetamol is required.

Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree followingsingle dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin isrequired when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax wasdelayed from 1 h to 3 h with liraglutide.

Liraglutide did not change the overall exposure of griseofulvin following administration of a singledose of griseofulvin 500 mg. Griseofulvin Cmax increased by 37% while median tmax did not change.

Dose adjustments of griseofulvin and other compounds with low solubility and high permeability arenot required.

A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUCby 16%; Cmax decreased by 31%. Digoxin median time to maximum concentration (tmax) was delayedfrom 1 h to 1.5 h. No dose adjustment of digoxin is required based on these results.

A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril

AUC by 15%; Cmax decreased by 27%. Lisinopril median tmax was delayed from 6 h to 8 h withliraglutide. No dose adjustment of lisinopril is required based on these results.

Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12 and 13%, respectively, followingadministration of a single dose of an oral contraceptive product. Tmax was delayed by 1.5 h withliraglutide for both compounds. There was no clinically relevant effect on the overall exposure ofeither ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to beunaffected when co-administered with liraglutide.

There is no clinical experience with the use of Xultophy, insulin degludec or liraglutide in pregnantwomen. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Xultophy shouldbe discontinued.

Animal reproduction studies with insulin degludec have not revealed any differences between insulindegludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies withliraglutide have shown reproductive toxicity, see section 5.3. The potential risk for humans isunknown.

There is no clinical experience with the use of Xultophy during breast-feeding. It is not knownwhether insulin degludec or liraglutide is excreted in human milk. Because of lack of experience,

Xultophy should not be used during breast-feeding.

In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma.

Animal studies have shown that the transfer of liraglutide and metabolites of close structuralrelationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-relatedreduction of neonatal growth in suckling rat pups (see section 5.3).

There is no clinical experience with Xultophy in relation to fertility.

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

Apart from a slight decrease in the number of live implants, animal studies with liraglutide did notindicate harmful effects with respect to fertility.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This mayconstitute a risk in situations where these abilities are of special importance (e.g. driving a car or usingmachines).

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 Xultophy clinical development programme included approximately 1,900 patients treated with

Xultophy.

The most frequently reported adverse reactions during treatment with Xultophy were hypoglycaemiaand gastrointestinal adverse reactions (see section ‘Description of selected adverse reactions’ below).

Adverse reactions associated with Xultophy are given below, listed by system organ class andfrequency. Frequency categories are defined as: Very common (≥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).

Table 1 Adverse reactions reported in phase 3 controlled studies

MedDRA System organ class Frequency Adverse reaction

Immune system disorders Uncommon Urticaria

Uncommon Hypersensitivity

Unknown Anaphylactic reaction

Metabolism and nutrition Very common Hypoglycaemiadisorders Common Decreased appetite

Uncommon Dehydration

Gastrointestinal disorders Common Nausea, diarrhoea, vomiting, constipation,dyspepsia, gastritis, abdominal pain,gastroesophageal reflux disease, abdominaldistension

Uncommon Eructation, flatulence

Unknown Pancreatitis (including necrotisingpancreatitis )

Hepatobiliary disorders Uncommon Cholelithiasis

Uncommon Cholecystitis

Skin and subcutaneous tissue Uncommon Rashdisorders Uncommon Pruritus

Uncommon Lipodystrophy acquired

Not known Cutaneous amyloidosis†

General disorders and Common Injection site reactionadministration site condition Unknown Peripheral oedema

Investigation Common Increased lipase

Common Increased amylase

Uncommon Increased heart rate† ADR from postmarketing sources.

Hypoglycaemia may occur if the Xultophy dose is higher than required. Severe hypoglycaemia maylead to unconsciousness and/or convulsions and may result in temporary or permanent impairment ofbrain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They mayinclude cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness orweakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes,headache, nausea and palpitation. For frequencies of hypoglycaemia, please see section 5.1.

Allergic reactions (manifested with signs and symptoms such as urticaria (0.3% of patients treatedwith Xultophy), rash (0.7%), pruritus (0.5%) and/or swelling of the face (0.2%)) have been reportedfor Xultophy. Few cases of anaphylactic reactions with additional symptoms such as hypotension,palpitations, dyspnoea, and oedema have been reported during marketed use of liraglutide.

Anaphylactic reactions may potentially be life threatening.

Gastrointestinal adverse reactions may occur more frequently at the beginning of Xultophy therapyand usually diminish within a few days or weeks on continued treatment. Nausea was reported in 7.8%of patients and was transient in nature for most patients. The proportion of patients reporting nauseaper week at any point during treatment was below 4%. Diarrhoea and vomiting were reported in 7.5%and 3.9% of patients, respectively. The frequency of nausea and diarrhoea was ‘Common’ for

Xultophy and ‘Very common’ for liraglutide. In addition, constipation, dyspepsia, gastritis, abdominalpain, gastroesophageal reflux disease, abdominal distension, eructation, flatulence and decreasedappetite have been reported in up to 3.6% of patients treated with Xultophy.

Injection site reactions (including injection site haematoma, pain, haemmorrhage, erythema, nodules,swelling, discolouration, pruritus, warmth and injection site mass) have been reported in 2.6% ofpatients treated with Xultophy. These reactions were usually mild and transitory and they normallydisappear during continued treatment.

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).

Mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed in clinical trialswith Xultophy. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk ofcardiovascular events was observed with liraglutide (a component of Xultophy) (see section 5.1).

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.

Limited data are available with regard to overdose of Xultophy.

Hypoglycaemia may develop if a patient is dosed with more Xultophy 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 sugar-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: A10AE56

Xultophy is a combination product consisting of insulin degludec and liraglutide havingcomplementary mechanisms of action to improve glycaemic control.

Insulin degludec is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection,resulting in a depot from which insulin degludec is continuously and slowly absorbed into thecirculation leading to a flat and stable glucose-lowering effect of insulin degludec with a low day-to-day variability in insulin action.

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 degludec is due to the facilitated uptake of glucosefollowing the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibitionof glucose output from the liver.

Liraglutide is a Glucagon-Like Peptide-1 (GLP-1) analogue with 97% sequence homology to human

GLP-1 that binds to and activates the GLP-1 receptor (GLP-1R). Following subcutaneousadministration, the protracted action profile is based on three mechanisms: self-association, whichresults in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidylpeptidase IV (DPP-IV) and neutral endopeptidase (NEP) enzymes, resulting in a long plasma half-life.

Liraglutide action is mediated via a specific interaction with GLP-1 receptors and improves glycaemiccontrol by lowering fasting and postprandial blood glucose. Liraglutide stimulates insulin secretionand lowers inappropriately high glucagon secretion in a glucose-dependent manner. Thus, when bloodglucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, duringhypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. Themechanism of blood glucose-lowering also involves a minor delay in gastric emptying.

Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger andlowered energy intake.

GLP-1 is a physiological regulator of appetite and food intake, but the exact mechanism of action isnot entirely clear. In animal studies, peripheral administration of liraglutide led to uptake in specificbrain regions involved in regulation of appetite, where liraglutide, via specific activation of the GLP-1R, increased key satiety and decreased key hunger signals, thereby leading to lower body weight.

GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, andkidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression andreduced inflammation in the plaque. In addition, liraglutide had a beneficial effect on plasma lipids.

Liraglutide did not reduce the plaque size of already established plaques.

Xultophy has a stable pharmacodynamic profile with a duration of action reflecting the combination ofthe individual action profiles of insulin degludec and liraglutide that allows for administration of

Xultophy once daily at any time of the day with or without meals. Xultophy improves glycaemiccontrol through the sustained lowering of fasting plasma glucose levels and postprandial glucose levelsafter all meals.

Postprandial glucose reduction was confirmed in a 4 hour standardised meal test substudy in patientsuncontrolled on metformin alone or in combination with pioglitazone. Xultophy decreased thepostprandial plasma glucose excursion (mean over 4 hours) significantly more than insulin degludec.

The results were similar for Xultophy and liraglutide.

The safety and efficacy of Xultophy were evaluated in seven randomised, controlled, parallel groupphase 3 trials in different populations of subjects with type 2 diabetes defined by previous antidiabetestreatment. Comparator treatments comprised basal insulin, GLP-1 RA therapy, placebo and a basalbolus regimen. The trials were of 26 weeks duration randomising between 199 and 833 patients to

Xultophy. One study was further extended to 52 weeks. In all trials, the starting dose was givenaccording to label and a twice-weekly titration regimen for Xultophy was used (see Table 2). Thesame titration algorithm was applied for basal insulin comparators. In six studies, Xultophy producedclinically and statistically significant improvements in glycaemic control versus comparators asmeasured by glycated haemaglobin A1c (HbA1c), whereas one study demonstrated a similar reductionof HbA1c in both treatment arms.

Table 2 Titration of Xultophy

Pre-breakfast plasma glucose* Dose adjustment (twice weekly)mmol/L mg/dL Xultophy (dose steps)<4.0 <72 -24.0-5.0 72-90 0>5.0 >90 +2

*Self-measured plasma glucose. In the trial investigating Xultophy as add on to sulfonylurea the target was 4.0-6.0 mmol/L

* Glycaemic control

Add-on to oral glucose-lowering medicinal products

Adding Xultophy to metformin alone or in combination with pioglitazone in a 26-week randomised,controlled, open-label trial resulted in 60.4% of patients treated with Xultophy reaching a target of

HbA1c <7% without confirmed hypoglycaemic episodes after 26 weeks of treatment. The proportionwas significantly larger than observed with insulin degludec (40.9%, odds ratio 2.28, p <0.0001) andsimilar to that observed with liraglutide (57.7%, odds ratio 1.13, p=0.3184). The key results of the trialare listed in Figure 1 and Table 3.

Rates of confirmed hypoglycaemia were lower with Xultophy than with insulin degludec irrespectiveof the glycaemic control, see Figure 1. The rate per patient year of exposure (percentage of patients) ofsevere hypoglycaemia defined as an episode requiring assistance of another person was 0.01(2 patients out of 825) for Xultophy, 0.01 (2 patients out of 412) for insulin degludec and 0.00(0 patients out of 412) for liraglutide. The rate of nocturnal hypoglycaemic events was similar with

Xultophy and insulin degludec treatment.

Patients treated with Xultophy overall experienced less gastrointestinal side effects than patientstreated with liraglutide. This might be due to the slower increase in the dose of the liraglutidecomponent during treatment initiation when using Xultophy as compared to using liraglutide alone.

The efficacy and safety of Xultophy were sustained up to 52 weeks of treatment. The reduction in

HbA1c from baseline to 52 weeks was 1.84% with Xultophy with an estimated treatment difference of

- 0.65% compared to liraglutide (p<0.0001) and -0.46% compared to insulin degludec (p<0.0001).

Body weight was reduced by 0.4 kg with an estimated treatment difference between Xultophy andinsulin degludec of -2.80 kg (p<0.0001), and the rate of confirmed hypoglycaemia remained 1.8 eventsper patient year of exposure maintaining a significant reduction in overall risk of confirmedhypoglycaemia compared to insulin degludec.

IDegLira

IDeg IDegLira obs. rate

Lira IDegLira

IDeg

IDeg obs. rate

Time since Randomisation (Week)

HbA1c (%) at end of treatment

The curves are mean hypo rates from a negative binomial model with unique treatmenttrajectories and the symbols are observed hypo rates vs. mean HbA1c by quartiles.

IDegLira=Xultophy, IDeg=insulin degludec, Lira=liraglutide, obs. rate=observed rate, PYE=patient year of exposure

Figure 1 Mean HbA1c (%) by treatment week (left) and rate of confirmed hypoglycaemia perpatient year of exposure vs mean HbA1c (%) (right) in patients with type 2 diabetes mellitusinadequately controlled on metformin alone or in combination with pioglitazone

Xultophy as add-on to sulfonylurea alone or in combination with metformin were studied in a 26-weekrandomised, placebo-controlled, double-blind trial. The key results of the trial are listed in Figure 2and Table 3.

IDegLira

Placebo

Time since Randomisation (Week)

IDegLira=Xultophy

Figure 2 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitusinadequately controlled on sulfonylurea alone or in combination with metformin

The rate per patient year of exposure (percentage of patients) of severe hypoglycaemia was 0.02 (2patients out of 288) for Xultophy and 0.00 (0 patients out of 146) for placebo.

Table 3 Results at 26-weeks - Add on to oral glucose-lowering medicinal products

Add on to sulfonylurea ±

Add on to metformin ± pioglitazone metformin

Xultophy Insulin degludec Liraglutide Xultophy Placebo

N 833 413 414 289 146

HbA1c (%)

Baseline→End of trial 8.3→6.4 8.3→6.9 8.3→7.0 7.9→6.4 7.9→7.4

Mean change -1.91 -1.44 -1.28 -1.45 -0.46

Estimated difference -0.47AB[-0.58; -0.36] -0.64AB[-0.75; -0.53] -1.02AB[-1.18; -0.87]

Patients (%) achieving

HbA1c <7%

All patients 80.6 65.1 60.4 79.2 28.8

Estimated odds ratio 2.38B [1.78; 3.18] 3.26B [2.45; 4.33] 11.95B [7.22; 19.77]

HbA1c (%) HbA1c (%)

Rate of hypoglycaemia (events per PYE)

Patients (%) achieving

HbA1c ≤6.5%

All patients 69.7 47.5 41.1 64.0 12.3

Estimated odds ratio 2.82B [2.17; 3.67] 3.98B [3.05; 5.18] 16.36B [9.05; 29.56]

Rate of confirmedhypoglycaemia* perpatient year ofexposure (percentage ofpatients) 1.80 (31.9%) 2.57 (38.6%) 0.22 (6.8%) 3.52 (41.7%) 1.35 (17.1%)

Estimated ratio 0.68AC [0.53; 0.87] 7.61B [5.17; 11.21] 3.74B [2.28; 6.13]

Body Weight (kg)

Baseline→End of trial 87.2→86.7 87.4→89.0 87.4→84.4 87.2→87.7 89.3→88.3

Mean change -0.5 1.6 -3.0 0.5 -1.0

Estimated difference -2.22AB [-2.64; -1.80] 2.44B [2.02; 2.86] 1.48B [0.90; 2.06]

FPG (mmol/L)

Baseline→End of trial 9.2→5.6 9.4→5.8 9.0→7.3 9.1→6.5 9.1→8.8

Mean change -3.62 -3.61 -1.75 -2.60 -0.31

Estimated difference -0.17 [-0.41; 0.07] -1.76B [-2.0; -1.53] -2.30B [-2.72; -1.89]

Dose End of trial

Insulin degludec (units) 38 53 - 28 -

Liraglutide (mg) 1.4 - 1.8 1.0 -

Estimated difference, -14.90AB [-17.14; -insulin degludec dose -12.66]

Baseline, End of trial and change values are observed Last observation carried forward. The 95% confidence interval is stated in ‘[]’

*Confirmed hypoglycaemia defined as severe hypoglycaemia (episode requiring assistance of another person) and/or minor hypoglycaemia(plasma glucose <3.1 mmol/L irrespective of symptoms)

A Endpoints with confirmed superiority of Xultophy vs comparator

B p<0.0001

C p<0.05

In an open label trial comparing the efficacy and safety of Xultophy and insulin glargine 100 units/mL,both as add-on to SGLT2i ± OAD, Xultophy was superior to insulin glargine in reducing mean HbA1cafter 26 weeks by 1.9% (from 8.2% to 6.3%) versus 1.7% (from 8.4% to 6.7%) with an estimatedtreatment difference of -0.36% [-0.50; -0.21]. Compared to baseline, Xultophy resulted in anunchanged mean body weight compared to a mean weight increase of 2.0 kg for patients treated withinsulin glargine (estimated treatment difference -1.92 kg [95% CI: -2.64; -1.19]). The percentage ofpatients experiencing severe or blood-glucose confirmed symptomatic hypoglycaemia was 12.9% inthe Xultophy group and 19.5% in the insulin glargine group (estimated treatment ratio 0.42 [95% CI:0.23; 0.75]). The mean daily insulin dose at end of trial was 36 units for patients treated with Xultophyand 54 units for patients treated with insulin glargine.

Transfer from GLP-1 receptor agonist therapy

Transfer from GLP-1 receptor agonist to Xultophy compared to unchanged GLP-1 receptor agonisttherapy (dosed according to label) were studied in a 26-weeks randomised, open-label trial in patientswith type 2 diabetes mellitus inadequately controlled on a GLP-1 receptor agonist and metforminalone (74.2%) or in combination with pioglitazone (2.5%), sulfonylurea (21.2%) or both (2.1%).

The key results of the trial are listed in Figure 3 and Table 4.

IDegLira

Unchanged GLP-1 RA

Time since Randomisation (Week)

IDegLira=Xultophy, GLP-1 RA=GLP-1 receptor agonist

Figure 3 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitus

HbA1c (%)inadequately controlled on GLP-1 receptor agonists

The rate per patient year of exposure (percentage of patients) of severe hypoglycaemia was 0.01(1 patient out of 291) for Xultophy and 0.00 (0 patients out of 199) for GLP-1 receptor agonists.

Table 4 Results at 26-weeks - Transfer from GLP-1 receptor agonists

Transfer from GLP-1 receptor agonist

Xultophy GLP-1 receptor agonist

N 292 146

HbA1c (%)

Baseline→End of trial 7.8→6.4 7.7→7.4

Mean change -1.3 -0.3

Estimated difference -0.94AB[-1.11; -0.78]

Patients (%) achieving HbA1c <7%

All patients 75.3 35.6

Estimated odds ratio 6.84B [4.28; 10.94]

Patients (%) achieving HbA1c ≤6.5%

All patients 63.0 22.6

Estimated odds ratio 7.53B [4.58; 12.38]

Rate of confirmed hypoglycaemia* perpatient year of exposure (percentage ofpatients) 2.82 (32.0%) 0.12 (2.8%)

Estimated ratio 25.36B [10.63; 60.51]

Body Weight (kg)

Baseline→End of trial 95.6→97.5 95.5→94.7

Mean change 2.0 -0.8

Estimated difference 2.89B [2.17; 3.62]

FPG (mmol/L)

Baseline→End of trial 9.0→6.0 9.4→8.8

Mean change -2.98 -0.60

Estimated difference -2.64B [-3.03; -2.25]

Dose End of trial

Insulin degludec (units) 43 GLP-1 receptor agonist dose was to

Liraglutide (mg) 1.6 be continued unchanged from

Estimated difference, insulin degludec dose baseline

Baseline, End of trial and change values are observed Last observation carried forward. The 95% confidence interval is stated in ‘[]’

*Confirmed hypoglycaemia defined as severe hypoglycaemia (episode requiring assistance of another person) and/or minor hypoglycaemia(plasma glucose <3.1 mmol/L irrespective of symptoms)

A Endpoints with confirmed superiority of Xultophy vs comparator

B p<0.001

Transfer from basal insulin therapies

Transfer of patients from insulin glargine (100 units/mL) to Xultophy or intensification of insulinglargine in patients inadequately controlled on insulin glargine (20-50 units) and metformin werestudied in a 26 week trial. The maximum allowed dose in the trial was 50 dose steps for Xultophywhereas there was no maximum dose for insulin glargine. 54.3% of patients treated with Xultophyreached the HbA1c target of <7% without confirmed hypoglycaemic episodes compared to 29.4% ofpatients treated with insulin glargine (odds ratio 3.24, p<0.001).

The key results of the trial are listed in Figure 4 and Table 5.

IDegLira

IGlar

Time since randomisation (week)

IDegLira=Xultophy, IGlar=insulin glargine

Figure 4 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitusinadequately controlled on insulin glargine

HbA1c (%)

The rate per patient year of exposure (percentage of patients) of severe hypoglycaemia was 0.00(0 patients out of 278) for Xultophy and 0.01 (1 patient out of 279) for insulin glargine. The rate ofnocturnal hypoglycaemic events was significantly lower with Xultophy compared to insulin glargine(estimated treatment ratio 0.17, p<0.001).

In a second trial, the transfer from basal insulin to Xultophy or insulin degludec was investigated in a26-week randomised, double-blind trial in patients inadequately controlled on basal insulin (20-40units) and metformin alone or in combination with sulfonylurea/glinides. Basal insulin andsulfonylurea/glinides were discontinued at randomisation. The maximum allowed dose was 50 dosesteps for Xultophy and 50 units for insulin degludec. 48.7% of patients treated with Xultophy reachedthe HbA1c target of <7% without confirmed hypoglycaemic episodes. This was a significantly higherproportion than observed with insulin degludec (15.6%, odds ratio 5.57, p<0.0001). The key results ofthe trial are listed in Figure 5 and Table 5.

IDegLira

IDeg

Time since Randomisation (Week)

IDegLira=Xultophy, IDeg=insulin degludec

Figure 5 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitusinadequately controlled on basal insulin

The rate per patient year of exposure (percentage of patients) of severe hypoglycaemia was 0.01(1 patient out of 199) for Xultophy and 0.00 (0 patients out of 199) for insulin degludec. The rate ofnocturnal hypoglycaemic events was similar with Xultophy and insulin degludec treatment.

Table 5 Results at 26-weeks - Transfer from basal insulin

Transfer from insulin glargine (100 Transfer from basal insulin (NPH, insulinunits/mL) detemir, insulin glargine)

Xultophy Insulin glargine, no Xultophy Insulin degludec, maximumlimitation to dose 50 units allowed

N 278 279 199 199

HbA1c (%)

Baseline→End of trial 8.4→6.6 8.2→7.1 8.7→6.9 8.8→8.0

Mean change -1.81 -1.13 -1.90 -0.89

Estimated difference -0.59AB[-0.74; -0.45] -1.05AB[-1.25; -0.84]

Patients (%) achieving

HbA1c <7%

All patients 71.6 47.0 60.3 23.1

Estimated odds ratio 3.45B [2.36; 5.05] 5.44B [3.42; 8.66]

Patients (%) achieving

HbA1c ≤6.5%

All patients 55.4 30.8 45.2 13.1

Estimated odds ratio 3.29B [2.27; 4.75] 5.66B [3.37; 9.51]

Rate of confirmedhypoglycaemia* perpatient year of exposure(percentage of patients) 2.23 (28.4%) 5.05 (49.1%) 1.53 (24.1%) 2.63 (24.6%)

Estimated ratio 0.43AB [0.30; 0.61] 0.66 [0.39; 1.13]

Body Weight (kg)

Baseline→End of trial 88.3→86.9 87.3→89.1 95.4→92.7 93.5→93.5

Mean change -1.4 1.8 -2.7 0.0

Estimated difference

HbA1c (%)

- 3.20AB [-3.77; -2.64] -2.51B [-3.21; -1.82]

FPG (mmol/L)

Baseline→End of trial 8.9→6.1 8.9→6.1 9.7→6.2 9.6→7.0

Mean change -2.83 -2.77 -3.46 -2.58

Estimated difference -0.01 [-0.35; 0.33] -0.73C [-1.19; -0.27]

Dose End of trial

Insulin (units) 41 66D 45 45

Liraglutide (mg) 1.5 - 1.7 -

Estimated difference, -25.47B [-28.90; -22.05] -0.02 [-1.88; 1.84]basal insulin dose

Baseline, End of trial and change values are observed Last observation carried forward. The 95% confidence interval is stated in ‘[]’

*Confirmed hypoglycaemia defined as severe hypoglycaemia (episode requiring assistance of another person) and/or minor hypoglycaemia(plasma glucose <3.1 mmol/L irrespective of symptoms)

A Endpoints with confirmed superiority of Xultophy vs comparator

B p<0.0001

C p<0.05

D The average pre-trial dose of insulin glargine was 32 units

Treatment with Xultophy compared to a basal-bolus insulin regimen consisting of basal insulin(insulin glargine 100 units/mL) in combination with bolus insulin (insulin aspart) studied in a 26-weektrial in patients with type 2 diabetes mellitus inadequately controlled on insulin glargine andmetformin demonstrated a similar reduction of HbA1c in the two groups (mean value from 8.2% to6.7% in both groups). In both groups 66%-67% achieved HbA1c < 7%. Compared to baseline, therewas a mean reduction in body weight of 0.9 kg for Xultophy and a mean increase of 2.6 kg for patientstreated with a basal-bolus regimen and the estimated treatment difference was -3.57 kg [95% CI: -4.19; -2.95]. The percentage of patients experiencing severe or blood-glucose confirmed symptomatichypoglycaemia was 19.8% in the Xultophy group and 52.6% in the basal-bolus insulin group, and theestimated rate ratio was 0.11 [95% CI: 0.08-0.17]. The total daily insulin dose at end of trial was40 units for patients treated with Xultophy and 84 units (52 units of basal insulin and 32 units of bolusinsulin) for patients treated with a basal-bolus insulin regimen.

* Cardiovascular Safety

No cardiovascular outcomes trials have been performed with Xultophy.

Liraglutide (Victoza)

The Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results(LEADER) trial, was a multicentre, placebo-controlled, double-blind clinical trial. 9,340 patients wererandomly allocated to either liraglutide (4,668) or placebo (4,672), both in addition to standards ofcare for HbA1c and cardiovascular (CV) risk factors. Primary outcome or vital status at end of trial wasavailable for 99.7% and 99.6% of participants randomised to liraglutide and placebo, respectively. Theduration of observation was minimum 3.5 years and up to a maximum of 5 years. The studypopulation included patients ≥65 years (n=4,329) and ≥75 years (n=836) and patients with mild(n=3,907), moderate (n=1,934) or severe (n=224) renal impairment. The mean age was 64 years andthe mean BMI was 32.5 kg/m². The mean duration of diabetes was 12.8 years.

The primary endpoint was the time from randomisation to first occurrence of any major adversecardiovascular events (MACE): CV death, non-fatal myocardial infarction or non-fatal stroke.

Liraglutide was superior in preventing MACE vs placebo (Figure 6).

Hazard Ratio Liraglutide N Placebo N(95% CI) (%) (%)

FAS 4668 4672(100) (100)

Primary endpoint - MACE 0.87 608 694(0.78-0.97) (13.0) (14.9)

Components of MACE:

Cardiovascular death 0.78 219 278(0.66-0.93) (4.7) (6.0)0.89

Non-fatal stroke 159 177(0.72-1.11) (3.4) (3.8)

Non-fatal myocardial infarction 0.88 281 317(0.75-1.03) (6.0) (6.8)

Expanded MACE 0.88 948 1062(0.81-0.96) (20.3) (22.7)

Additional components in expanded MACE:

Unstable angina pectoris (hospitalisation) 0.98 122 124(0.76-1.26) (2.6) (2.7)0.91 405 441

Coronary revascularisation (0.80-1.04) (8.7) (9.4)0.87 218 248

Heart failure (hospitalisation) (0.73-1.05) (4.7) (5.3)

Other secondary endpoints:

All cause death 0.85 381 447(0.74-0.97) (8.2) (9.6)0.95

Non-cardiovascular death 162 169(0.77-1.18) (3.5) (3.6)

FAS: full analysis set

CI: confidence interval 0.7 0.8 0.9 1 1.1 1.2

MACE: major adverse cardiovascular event Favours Liraglutide Favours Placebo%: proportion in percent of subjects with an event

N: number of subjects

Figure 6 Forest plot of analyses of individual cardiovascular event types - FAS population

A reduction in HbA1c from baseline to month 36 was observed with liraglutide vs placebo, in additionto standard of care (-1.16% vs -0.77%; estimated treatment difference [ETD] -0.40% [-0.45; -0.34]).

Insulin degludec (Tresiba)

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

At baseline, HbA1c was 8.4% in both treatment groups and after 2 years HbA1c was 7.5% both withinsulin 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 (0.75-1.11) 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 7 Forest plot of analysis of the composite 3-point MACE and individual cardiovascularendpoints in DEVOTE

* Insulin secretion/beta-cell function

Xultophy improves beta-cell function compared to insulin degludec as measured by the homeostasismodel assessment for beta-cell function (HOMA-β). Improved insulin secretion compared to insulindegludec in response to a standardised meal test was demonstrated in 260 patients with type 2 diabetesafter 52 weeks of treatment. No data is available beyond 52 weeks of treatment.

* Blood pressure

In patients inadequately controlled on metformin alone or in combination with pioglitazone, Xultophyreduced mean systolic blood pressure by 1.8 mmHg compared to a reduction of 0.7 mmHg withinsulin degludec and 2.7 mmHg with liraglutide. In patients inadequately controlled on sulfonylureaalone or in combination with metformin, the reduction was 3.5 mmHg with Xultophy and 3.2 mmHgwith placebo. The differences were not statistically significant. In three trials with patientsinadequately controlled on basal insulin, systolic blood pressure was reduced by 5.4 mmHg with

Xultophy and 1.7 mmHg with insulin degludec, with a statistically significant estimated treatmentdifference of -3.71 mmHg (p=0.0028), reduced by 3.7 mmHg with Xultophy vs 0.2 mmHg withinsulin glargine, with a statistically significant estimated treatment difference of -3.57 mmHg(p<0.001) and reduced by 4.5 mmHg with Xultophy vs 1.16 mmHg with insulin glargine U100 plusinsulin aspart, with a statistically significant estimated treatment difference of -3.70 mmHg(p=0.0003).

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

Xultophy in all subsets of the paediatric population for treatment of type 2 diabetes mellitus (seesection 4.2 for information on paediatric use).

Overall, the pharmacokinetics of insulin degludec and liraglutide were not affected in a clinicallyrelevant manner when administered as Xultophy compared with independent injections of insulindegludec and liraglutide.

The following reflects the pharmacokinetic properties of Xultophy unless stated that the presented datais from administration of insulin degludec or liraglutide alone.

The overall exposure of insulin degludec was equivalent following administration of Xultophy versusinsulin degludec alone while the Cmax was higher by 12%. The overall exposure of liraglutide wasequivalent following administration of Xultophy versus liraglutide alone while Cmax was lower by23%. The differences are considered of no clinical relevance since Xultophy is initiated and titratedaccording to the individual patient’s blood glucose targets.

Insulin degludec and liraglutide exposure increased proportionally with the Xultophy dose within thefull dose range based on a population pharmacokinetic analysis.

The pharmacokinetic profile of Xultophy is consistent with once-daily dosing and steady-stateconcentration of insulin degludec and liraglutide is reached after 2-3 days of daily administration.

Insulin degludec and liraglutide are extensively bound to plasma proteins (>99% and >98%,respectively).

Insulin degludec

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

Liraglutide

During 24 hours following administration of a single radiolabelled [3H]-liraglutide dose to healthysubjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites weredetected (≤9% and ≤5% of total plasma radioactivity exposure). Liraglutide is metabolised in a similarmanner to large proteins without a specific organ having been identified as major route of elimination.

The half-life of insulin degludec is approximately 25 hours and the half-life of liraglutide isapproximately 13 hours.

Age had no clinically relevant effect on the pharmacokinetics of Xultophy based on results from apopulation pharmacokinetic analysis including adult patients up to 83 years treated with Xultophy.

Gender had no clinically relevant effect on the pharmacokinetics of Xultophy based on results from apopulation pharmacokinetic analysis.

Ethnic origin had no clinically relevant effect on the pharmacokinetics of Xultophy based on resultsfrom a population pharmacokinetic analysis including White, Black, Indian, Asian and Hispanicgroups.

Insulin degludec

There is no difference in the pharmacokinetics of insulin degludec between healthy subjects andpatients with renal impairment.

Liraglutide

Liraglutide exposure was reduced in patients with renal impairment compared to individuals withnormal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 26%, in patients withmild (creatinine clearance, CrCl 50-80 mL/min), moderate (CrCl 30-50 mL/min), and severe (CrCl<30 mL/min) renal impairment and in end-stage renal disease requiring dialysis, respectively.

Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment(CrCl 30-59 mL/min) had 26% lower liraglutide exposure when compared with a separate trialincluding patients with type 2 diabetes with normal renal function or mild renal impairment.

Insulin degludec

There is no difference in the pharmacokinetics of insulin degludec between healthy subjects andpatients with hepatic impairment.

Liraglutide

The pharmacokinetics of liraglutide was evaluated in patients with varying degrees of hepaticimpairment in a single-dose trial. Liraglutide exposure was decreased by 13-23% in patients with mildto moderate hepatic impairment compared to healthy subjects. Exposure was significantly lower (44%)in patients with severe hepatic impairment (Child Pugh score >9).

No studies have been performed with Xultophy in children and adolescents below 18 years of age.

The non-clinical development programme for insulin degludec/liraglutide included pivotalcombination toxicity studies of up to 90 days duration in a single relevant species (Wistar rats) tosupport the clinical development programme. Local tolerance was assessed in rabbits and pigs.

Non-clinical safety data revealed no safety concern for humans based on repeated dose toxicitystudies.

The local tissue reactions in the two studies in rabbits and pigs, respectively, were limited to mildinflammatory reactions.

No studies have been conducted with the insulin degludec/liraglutide combination to evaluatecarcinogenesis, mutagenesis or impairment of fertility. The following data are based upon studies withinsulin degludec and liraglutide individually.

Insulin degludec

Non-clinical data reveal no safety concern 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 unchanged compared tohuman insulin.

Liraglutide

Non-clinical data reveal no special hazards for human based on conventional studies of safetypharmacology, repeat-dose toxicity, or genotoxicity. Non-lethal thyroid C-cell tumours were seen in2-year carcinogenicity studies in rats and mice. In rats, a no observed adverse effect level (NOAEL)was not observed. These tumours were not seen in monkeys treated for 20 months. These findings inrodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which rodentsare particularly sensitive. The relevance for humans is likely to be low but cannot be completelyexcluded. No other treatment-related tumours have been found.

Animal studies did not indicate direct harmful effects with respect to fertility but slightly increasedearly embryonic deaths at the highest dose. Dosing with liraglutide during mid-gestation caused areduction in maternal weight and foetal growth with equivocal effects on ribs in rats and skeletalvariation in the rabbit. Neonatal growth was reduced in rats while exposed to liraglutide, and persistedin the post-weaning period in the high dose group. It is unknown whether the reduced pup growth iscaused by reduced pup milk intake due to a direct GLP-1 effect or reduced maternal milk productiondue to decreased caloric intake.

Glycerol

Phenol

Zinc acetate

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

Substances added to Xultophy may cause degradation of the active substances.

Xultophy must not be added to infusion fluids.

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

2 years.

After first opening, the medicinal product can be stored for 21 days at a maximum temperature of30°C. The medicinal product should be discarded 21 days after first opening.

Before first opening: Store in a refrigerator (2°C - 8°C). Keep away from the freezing element. Do notfreeze. Keep the cap on the pre-filled pen in order to protect from light.

After first opening: Store at a maximum of 30°C or store in a refrigerator (2°C - 8°C). Do not freeze.

Keep the cap on the pre-filled pen in order to protect from light.

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

3 mL solution in a cartridge (type 1 glass) with a plunger (halobutyl) and a stopper(halobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polypropylene,polycarbonate and acrylonitrile butadiene styrene.

Pack sizes of 1, 3, 5 and multipack containing 10 (2 packs of 5) pre-filled pens.

Not all pack sizes may be marketed.

The pre-filled pen is designed to be used with NovoTwist or NovoFine injection needles up to a lengthof 8 mm and as thin as 32G.

The pre-filled pen is for use by one person only.

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

Xultophy 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 unused medicinal product or waste material should be disposed of in accordance with localrequirements.

For detailed instructions for use, see the package leaflet.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/14/947/001

EU/1/14/947/002

EU/1/14/947/003

EU/1/14/947/004

Date of first authorisation: 18 September 2014

Date of latest renewal: 08 July 2019

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

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