Xultophy

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Xultophy 100 units/mL + 3.6 mg/mL solution for injection. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection. 
 
Clear, colourless, isotonic solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Xultophy is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus 
to improve glycaemic control as an adjunct to diet and exercise in addition to other oral medicinal 
products for the treatment of diabetes. For study results with respect to combinations, effects on 
glycaemic control, and the populations studied, see sections 4.4, 4.5 and 5.1. 
 
4.2 Posology and method of administration 
 
Posology 
 
Xultophy is given once daily by subcutaneous administration. Xultophy can be administered at any 
time 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 to 
optimise glycaemic control via dose adjustment based on fasting plasma glucose.  
 
Adjustment of dose may be necessary if patients undertake increased physical activity, change their 
usual diet or during concomitant illness. 
 
Patients who forget a dose are advised to take it upon discovery and then resume their usual once-daily 
dosing schedule. A minimum of 8 hours between injections should always be ensured. This also 
applies 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 and 
0.036 mg of liraglutide. The pre-filled pen can provide from 1 up to 50 dose steps in one injection in 
increments of one dose step. The maximum daily dose of Xultophy is 50 dose steps (50 units insulin 
degludec 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 



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The recommended starting dose of Xultophy is 10 dose steps (10 units insulin degludec and 0.36 mg 
liraglutide).  
 
Xultophy can be added to existing oral antidiabetic treatment. When Xultophy is added to sulfonylurea 
therapy, 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. When 
transferring from a GLP-1 receptor agonist, the recommended starting dose of Xultophy is 16 dose 
steps (16 units insulin degludec and 0.6 mg liraglutide) (see section 5.1). The recommended starting 
dose 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 be 
initiated at the moment the next dose of the long-acting GLP-1 receptor agonist would have been 
taken. 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. When 
transferring from any other insulin therapy that includes a basal insulin component, the recommended 
starting dose of Xultophy is 16 dose steps (16 units insulin degludec and 0.6 mg liraglutide) (see 
section 4.4 and 5.1). The recommended starting dose should not be exceeded, but may be reduced to 
avoid hypoglycaemia in selected cases. Close glucose monitoring is recommended during the transfer 
and in the following weeks.  
 
Special populations 
 
Elderly patients (≥65 years old) 
Xultophy can be used in elderly patients. Glucose monitoring is to be intensified and the dose adjusted 
on an individual basis.  
 
Renal impairment  
When Xultophy is used in patients with mild, moderate or severe renal impairment, glucose 
monitoring is to be intensified and the dose adjusted on an individual basis. Xultophy cannot be 
recommended for use in patients with end-stage renal disease (see sections 5.1 and 5.2). 
 
Hepatic impairment  
Xultophy can be used in patients with mild or moderate hepatic impairment. Glucose monitoring is to 
be intensified and the dose adjusted on an individual basis.  
Due to the liraglutide component, Xultophy is not recommended for use in patients with severe hepatic 
impairment (see section 5.2). 
 
Paediatric population  
There is no relevant use of Xultophy in the paediatric population.  
 
Method of administration 
 
Xultophy is for subcutaneous use only. Xultophy must not be administered intravenously or 
intramuscularly. 
 
Xultophy is administered subcutaneously by injection in the thigh, the upper arm or the abdomen. 
Injection sites are always to be rotated within the same region in order to reduce the risk of 
lipodystrophy. For further instructions on administration, 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 increases 
the 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 package 



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leaflet (see section 6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to either or both active substances or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Xultophy should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic 
ketoacidosis. 
 
Hypoglycaemia 
 
Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal or 
unplanned 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. Concomitant 
diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require 
changes of the Xultophy dose. Patients whose blood glucose control is greatly improved (e.g. by 
intensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia and 
must be advised accordingly. Usual warning symptoms (see section 4.8) of hypoglycaemia may 
disappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delay 
recovery from hypoglycaemia. 
 
Hyperglycaemia 
 
Inadequate dosing and/or discontinuation of antidiabetic treatment may lead to hyperglycaemia and 
potentially to hyperosmolar coma. In case of discontinuation of Xultophy, ensure that instruction for 
initiation of alternative antidiabetic treatment is followed. Furthermore, concomitant illness, especially 
infections, may lead to hyperglycaemia and thereby cause an increased requirement for antidiabetic 
treatment. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or 
days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry 
skin, 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, which 
is potentially lethal. 
 
Combination of pioglitazone and insulin medicinal products 
 
Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin 
medicinal products, especially in patients with risk factors for development of cardiac failure. This 
should 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, weight 
gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms 
occurs. 
 
Eye disorder 
 
Intensification of therapy with insulin, a component of Xultophy, with abrupt improvement in 
glycaemic 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/or 
liraglutide. In rare cases, the presence of such antibodies may necessitate adjustment of the Xultophy 
dose in order to correct a tendency to hyper- or hypoglycaemia. Very few patients developed insulin 
degludec specific antibodies, antibodies cross-reacting to human insulin or anti-liraglutide antibodies 



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following treatment with Xultophy. Antibody formation has not been associated with reduced efficacy 
of Xultophy. 
 
Acute pancreatitis 
 
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 is 
suspected, Xultophy should be discontinued; if acute pancreatitis is confirmed, Xultophy should not be 
restarted.  
 
Thyroid adverse events 
 
Thyroid adverse events, such as goitre have been reported in clinical trials with GLP-1 receptor 
agonists including liraglutide, and in particular in patients with pre-existing thyroid disease. Xultophy 
should 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 diabetic 
gastroparesis. Xultophy is therefore not recommended in these patients.  
 
Dehydration 
 
Signs and symptoms of dehydration, including renal impairment and acute renal failure have been 
reported 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 to 
gastrointestinal 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 accidental 
mix-ups between Xultophy and other injectable diabetes medicinal products. 
 
Patients must visually verify the dialled units on the dose counter of the pen. Therefore, the 
requirement for patients to self-inject is that they can read the dose counter on the pen. Patients who 
are blind or have poor vision must be instructed to always get help/assistance from another person who 
has good vision and is trained in using the insulin device. 
 
To avoid dosing errors and potential overdose, patients and healthcare professionals should never use a 
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 for 
use accompanying the package leaflet (see section 6.6). 
 
Populations not studied 
 
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. 
 
Excipients 
 
Xultophy contains less than 1 mmol sodium (23 mg) per dose, therefore the medicinal product is 
essentially ‘sodium-free’. 
 
Traceability 



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In order to improve the traceability of biological medicinal products, the name and the batch number 
of the administered product should be clearly recorded. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Pharmacodynamic interactions 
 
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, angiotensin 
converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides. 
 
The following substances may increase the Xultophy requirement: 
Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth 
hormones 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. 
 
Pharmacokinetic interactions 
 
In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction 
and protein binding is low for both liraglutide and insulin degludec. 
 
The small delay of gastric emptying with liraglutide may influence absorption of concomitantly 
administered oral medicinal products. Interaction studies did not show any clinically relevant delay of 
absorption.  
 
Warfarin and other coumarin derivatives 
No interaction study has been performed. A clinically relevant interaction with active substances with 
poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation 
of Xultophy treatment in patients on warfarin or other coumarin derivatives more frequent monitoring 
of INR (International Normalised Ratio) is recommended. 
 
Paracetamol  
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 dose 
adjustment for concomitant use of paracetamol is required. 
 
Atorvastatin 
Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following 
single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is 
required when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax was 
delayed from 1 h to 3 h with liraglutide. 
 
Griseofulvin 
Liraglutide did not change the overall exposure of griseofulvin following administration of a single 
dose 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 are 
not required. 
 
Digoxin 
A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC 
by 16%; Cmax decreased by 31%. Digoxin median time to maximum concentration (tmax) was delayed 



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from 1 h to 1.5 h. No dose adjustment of digoxin is required based on these results. 
 
Lisinopril 
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 with 
liraglutide. No dose adjustment of lisinopril is required based on these results. 
 
Oral contraceptives 
Liraglutide lowered ethinylestradiol and levonorgestrel Cmax by 12 and 13%, respectively, following 
administration of a single dose of an oral contraceptive product. Tmax was delayed by 1.5 h with 
liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of 
either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be 
unaffected when co-administered with liraglutide. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
There is no clinical experience with the use of Xultophy, insulin degludec or liraglutide in pregnant 
women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Xultophy should 
be discontinued. 
 
Animal reproduction studies with insulin degludec have not revealed any differences between insulin 
degludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies with 
liraglutide have shown reproductive toxicity, see section 5.3. The potential risk for humans is 
unknown. 
 
Breast-feeding 
 
There is no clinical experience with the use of Xultophy during breast-feeding. It is not known 
whether 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 structural 
relationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-related 
reduction of neonatal growth in suckling rat pups (see section 5.3). 
 
Fertility 
 
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 not 
indicate harmful effects with respect to fertility. 
 
4.7 Effects on ability to drive and use machines 
 
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 a car or using 
machines). 
 
Patients must be advised to take precautions to avoid hypoglycaemia while driving. This is particularly 
important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or 
have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these 
circumstances. 
 
4.8 Undesirable effects 
 



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Summary of the safety profile  
 
The Xultophy clinical development programme included approximately 1,900 patients treated with 
Xultophy.  
 
The most frequently reported adverse reactions during treatment with Xultophy were hypoglycaemia 
and gastrointestinal adverse reactions (see section ‘Description of selected adverse reactions’ below). 
 
Tabulated list of adverse reactions 
 
Adverse reactions associated with Xultophy are given below, listed by system organ class and 
frequency. 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 
disorders 

Very common Hypoglycaemia 
Common Decreased appetite 
Uncommon Dehydration 

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

Uncommon Eructation, flatulence 
Unknown Pancreatitis (including necrotising 

pancreatitis ) 
Hepatobiliary disorders Uncommon Cholelithiasis 

Uncommon Cholecystitis 
Skin and subcutaneous tissue 
disorders 

Uncommon Rash 
Uncommon Pruritus 
Uncommon Lipodystrophy acquired 

General disorders and 
administration site condition 

Common Injection site reaction 
Unknown Peripheral oedema 

Investigation Common Increased lipase 
Common Increased amylase 
Uncommon Increased heart rate  

 
Description of selected adverse reactions  
 
Hypoglycaemia 
Hypoglycaemia may occur if the Xultophy dose is higher than required. Severe hypoglycaemia may 
lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of 
brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. 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. For frequencies of hypoglycaemia, please see section 5.1. 
 
Allergic reactions 
Allergic reactions (manifested with signs and symptoms such as urticaria (0.3% of patients treated 
with Xultophy), rash (0.7%), pruritus (0.5%) and/or swelling of the face (0.2%)) have been reported 
for Xultophy. Few cases of anaphylactic reactions with additional symptoms such as hypotension, 



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palpitations, dyspnoea, and oedema have been reported during marketed use of liraglutide. 
Anaphylactic reactions may potentially be life threatening.  
 
Gastrointestinal adverse reactions 
Gastrointestinal adverse reactions may occur more frequently at the beginning of Xultophy therapy 
and 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 nausea 
per 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, abdominal 
pain, gastroesophageal reflux disease, abdominal distension, eructation, flatulence and decreased 
appetite have been reported in up to 3.6% of patients treated with Xultophy.  
 
Injection site reactions 
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% of 
patients treated with Xultophy. These reactions were usually mild and transitory and they normally 
disappear during continued treatment. 
 
Lipodystrophy 
Lipodystrophy (including lipohypertrophy, lipoatrophy) may occur at the injection site. Continuous 
rotation of the injection site within the particular injection area may help to reduce the risk of 
developing these reactions. 
 
Increased heart rate  
Mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed in clinical trials 
with Xultophy. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk of 
cardiovascular events was observed with liraglutide (a component of Xultophy) (see section 5.1). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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 products 

containing sugar. It is therefore recommended that the patient always carries sugar-containing 
products 

• Severe hypoglycaemic episodes, where the patient is not able to treat himself, can be treated 
with glucagon (0.5 to 1 mg) given intramuscularly or subcutaneously by a trained person, or 
with glucose given intravenously by a healthcare professional. Glucose must be 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 the patient in 
order to prevent a relapse. 

 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 

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Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting. 
ATC code: A10AE56  
 
Mechanism of action 
 
Xultophy is a combination product consisting of insulin degludec and liraglutide having 
complementary 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 the 
circulation 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 same 
pharmacological effects as human insulin.  
 
The blood glucose-lowering effect of insulin degludec is due to the facilitated uptake of glucose 
following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition 
of 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 subcutaneous 
administration, the protracted action profile is based on three mechanisms: self-association, which 
results in slow absorption; binding to albumin; and higher enzymatic stability towards the dipeptidyl 
peptidase 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 glycaemic 
control by lowering fasting and postprandial blood glucose. Liraglutide stimulates insulin secretion 
and lowers inappropriately high glucagon secretion in a glucose-dependent manner. Thus, when blood 
glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during 
hypoglycaemia liraglutide diminishes insulin secretion and does not impair glucagon secretion. The 
mechanism 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 and 
lowered energy intake. 
 
GLP-1 is a physiological regulator of appetite and food intake, but the exact mechanism of action is 
not entirely clear. In animal studies, peripheral administration of liraglutide led to uptake in specific 
brain 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, and 
kidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression and 
reduced 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. 
 
Pharmacodynamic effects 
 
Xultophy has a stable pharmacodynamic profile with a duration of action reflecting the combination of 
the 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 glycaemic 
control through the sustained lowering of fasting plasma glucose levels and postprandial glucose levels 
after all meals.  
 
Postprandial glucose reduction was confirmed in a 4 hour standardised meal test substudy in patients 
uncontrolled on metformin alone or in combination with pioglitazone. Xultophy decreased the 
postprandial plasma glucose excursion (mean over 4 hours) significantly more than insulin degludec. 



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The results were similar for Xultophy and liraglutide. 
 
Clinical efficacy and safety 
 
The safety and efficacy of Xultophy were evaluated in seven randomised, controlled, parallel group 
phase 3 trials in different populations of subjects with type 2 diabetes defined by previous antidiabetes 
treatment. Comparator treatments comprised basal insulin, GLP-1 RA therapy, placebo and a basal 
bolus 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 given 
according to label and a twice-weekly titration regimen for Xultophy was used (see Table 2). The 
same titration algorithm was applied for basal insulin comparators. In six studies, Xultophy produced 
clinically and statistically significant improvements in glycaemic control versus comparators as 
measured by glycated haemaglobin A1c (HbA1c), whereas one study demonstrated a similar reduction 
of 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 -2 
4.0–5.0 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 proportion 
was significantly larger than observed with insulin degludec (40.9%, odds ratio 2.28, p <0.0001) and 
similar to that observed with liraglutide (57.7%, odds ratio 1.13, p=0.3184). The key results of the trial 
are listed in Figure 1 and Table 3. 
 
Rates of confirmed hypoglycaemia were lower with Xultophy than with insulin degludec irrespective 
of the glycaemic control, see Figure 1. The rate per patient year of exposure (percentage of patients) of 
severe 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 patients 
treated with liraglutide. This might be due to the slower increase in the dose of the liraglutide 
component 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 and 
insulin degludec of -2.80 kg (p<0.0001), and the rate of confirmed hypoglycaemia remained 1.8 events 
per patient year of exposure maintaining a significant reduction in overall risk of confirmed 
hypoglycaemia compared to insulin degludec. 
 



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H

bA
1c

 (%
) 

Time since Randomisation (Week) 

IDegLira 
IDeg 
Lira 

 

 

R
at

e 
of

 h
yp

og
ly

ca
em

ia
 (e

ve
nt

s 
pe

r P
Y

E)
 

HbA1c (%) at end of treatment 

IDegLira obs. rate 
IDegLira 
IDeg 
IDeg obs. rate 

The curves are mean hypo rates from a negative binomial model with unique treatment 
trajectories 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 per 
patient year of exposure vs mean HbA1c (%) (right) in patients with type 2 diabetes mellitus 
inadequately 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-week 
randomised, placebo-controlled, double-blind trial. The key results of the trial are listed in Figure 2 
and Table 3.  
 
 

H
bA

1c
 (%

) 

Time since Randomisation (Week) 

IDegLira 
Placebo 

 

 

IDegLira=Xultophy 
 
Figure 2 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitus 
inadequately 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 (2 
patients 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 metformin ± pioglitazone  Add on to sulfonylurea ± metformin 
 Xultophy Insulin degludec Liraglutide Xultophy Placebo 
N 833 413 414 289 146 
HbA1c (%) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
8.3→6.4 
-1.91 
 

 
8.3→6.9 
-1.44 
-0.47AB[-0.58; -0.36] 

 
8.3→7.0 
-1.28 
-0.64AB[-0.75; -0.53] 

 
7.9→6.4 
-1.45 
 

 
7.9→7.4 
-0.46 
-1.02AB[-1.18; -0.87]  

Patients (%) achieving 
HbA1c <7% 
All patients 
Estimated odds ratio 

 
 
80.6 
 

 
 
65.1 
2.38B [1.78; 3.18] 

 
 
60.4 
3.26B [2.45; 4.33] 

 
 
79.2 

 
 
28.8 
11.95B [7.22; 19.77]  

Patients (%) achieving 
HbA1c ≤6.5% 
All patients 
Estimated odds ratio 

 
 
69.7 
 

 
 
47.5 
2.82B [2.17; 3.67] 

 
 
41.1 
3.98B [3.05; 5.18] 

 
 
64.0 
 

 
 
12.3 
16.36B [9.05; 29.56]  

Rate of confirmed 
hypoglycaemia* per 
patient year of 

 
 

 
 

 
 

 
 

 
 



13 

exposure (percentage of 
patients) 
Estimated ratio 

 
 
1.80 (31.9%) 
 

 
 
2.57 (38.6%) 
0.68AC [0.53; 0.87] 

 
 
0.22 (6.8%) 
7.61B [5.17; 11.21] 

 
3.52 (41.7%) 

 
 
1.35 (17.1%) 
3.74B [2.28; 6.13]  

Body Weight (kg) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
87.2→86.7 
-0.5 
 

 
87.4→89.0 
1.6 
-2.22AB [-2.64; -1.80] 

 
87.4→84.4 
-3.0 
2.44B [2.02; 2.86] 

 
87.2→87.7 
0.5 

 
89.3→88.3 
-1.0 
1.48B [0.90; 2.06] 

FPG (mmol/L) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
9.2→5.6 
-3.62 
 

 
9.4→5.8 
-3.61 
-0.17 [-0.41; 0.07] 

 
9.0→7.3 
-1.75 
-1.76B [-2.0; -1.53] 

 
9.1→6.5 
-2.60 

 
9.1→8.8 
-0.31 
-2.30B [-2.72; -1.89] 

Dose End of trial 
Insulin degludec (units) 
Liraglutide (mg) 
Estimated difference, 
insulin degludec dose 

 
38 
1.4 
 
 

 
53 
- 
-14.90AB [-17.14; 
 -12.66] 

 
- 
1.8 
 
 

 
28 
1.0 
 
 

 
- 
- 
- 
 

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 HbA1c 
after 26 weeks by 1.9% (from 8.2% to 6.3%) versus 1.7% (from 8.4% to 6.7%) with an estimated 
treatment difference of -0.36% [-0.50; -0.21]. Compared to baseline, Xultophy resulted in an 
unchanged mean body weight compared to a mean weight increase of 2.0 kg for patients treated with 
insulin glargine (estimated treatment difference -1.92 kg [95% CI: -2.64; -1.19]). The percentage of 
patients experiencing severe or blood-glucose confirmed symptomatic hypoglycaemia was 12.9% in 
the 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 Xultophy 
and 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 agonist 
therapy (dosed according to label) were studied in a 26-weeks randomised, open-label trial in patients 
with type 2 diabetes mellitus inadequately controlled on a GLP-1 receptor agonist and metformin 
alone (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. 
 
 

H
bA

1c
 (%

) 

Time since Randomisation (Week) 

IDegLira 
Unchanged GLP-1 RA 

 

 

IDegLira=Xultophy, GLP-1 RA=GLP-1 receptor agonist 
 
Figure 3 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitus 
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.  
 



14 

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 
Mean change 
Estimated difference 

 
7.8→6.4 
-1.3 
 

 
7.7→7.4 
-0.3 
-0.94AB[-1.11; -0.78]  

Patients (%) achieving HbA1c <7% 
All patients 
Estimated odds ratio 

 
75.3 

 
35.6 
6.84B [4.28; 10.94]  

Patients (%) achieving HbA1c ≤6.5% 
All patients 
Estimated odds ratio 

 
63.0 
 

 
22.6 
7.53B [4.58; 12.38]  

Rate of confirmed hypoglycaemia* per 
patient year of exposure (percentage of 
patients) 
Estimated ratio 

 
 
2.82 (32.0%) 
 

 
 
0.12 (2.8%) 
25.36B [10.63; 60.51]  

Body Weight (kg) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
95.6→97.5 
2.0 

 
95.5→94.7 
-0.8 
2.89B [2.17; 3.62] 

FPG (mmol/L) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
9.0→6.0 
-2.98 

 
9.4→8.8 
-0.60 
-2.64B [-3.03; -2.25] 

Dose End of trial 
Insulin degludec (units) 
Liraglutide (mg) 
Estimated difference, insulin degludec dose 

 
43 
1.6 
 
 

GLP-1 receptor agonist dose was to 
be continued unchanged from 
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 insulin 
glargine in patients inadequately controlled on insulin glargine (20-50 units) and metformin were 
studied in a 26 week trial. The maximum allowed dose in the trial was 50 dose steps for Xultophy 
whereas there was no maximum dose for insulin glargine. 54.3% of patients treated with Xultophy 
reached the HbA1c target of <7% without confirmed hypoglycaemic episodes compared to 29.4% of 
patients 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.  
 
 

H
bA

1c
 (%

) 

Time since randomisation (week) 

IDegLira 
IGlar 

  
IDegLira=Xultophy, IGlar=insulin glargine 
 
Figure 4 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitus 
inadequately controlled on insulin glargine 
 
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 of 
nocturnal hypoglycaemic events was significantly lower with Xultophy compared to insulin glargine 
(estimated treatment ratio 0.17, p<0.001). 
 



15 

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

 

 

H
bA

1c
 (%

) 

Time since Randomisation (Week) 

IDegLira 
IDeg 

 

 

IDegLira=Xultophy, IDeg=insulin degludec 
 
Figure 5 Mean HbA1c (%) by treatment week in patients with type 2 diabetes mellitus 
inadequately 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 of 
nocturnal 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 units/mL) 
 Transfer from basal insulin (NPH, insulin 

detemir, insulin glargine) 

 Xultophy Insulin glargine, no limitation to dose 
 Xultophy Insulin degludec, maximum 

50 units allowed 
N 278 279  199 199 
HbA1c (%) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
8.4→6.6 
-1.81 
 

 
8.2→7.1 
-1.13 
-0.59AB[-0.74; -0.45]  

  
8.7→6.9 
-1.90 
 

 
8.8→8.0 
-0.89 
-1.05AB[-1.25; -0.84]  

Patients (%) achieving 
HbA1c <7% 
All patients 
Estimated odds ratio 

 
 
71.6 

 
 
47.0 
3.45B [2.36; 5.05]  

  
 
60.3 

 
 
23.1 
5.44B [3.42; 8.66]  

Patients (%) achieving 
HbA1c ≤6.5% 
All patients 
Estimated odds ratio 

 
 
55.4 
 

 
 
30.8 
3.29B [2.27; 4.75]  

  
 
45.2 
 

 
 
13.1 
5.66B [3.37; 9.51]  

Rate of confirmed 
hypoglycaemia* per 
patient year of exposure 
(percentage of patients) 
Estimated ratio 

 
 
 
2.23 (28.4%) 
 

 
 
 
5.05 (49.1%) 
0.43AB [0.30; 0.61]  

  
 
 
1.53 (24.1%) 
 

 
 
 
2.63 (24.6%) 
0.66 [0.39; 1.13]  

Body Weight (kg) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
88.3→86.9 
-1.4 

 
87.3→89.1 
1.8 
-3.20AB [-3.77; -2.64] 

  
95.4→92.7 
-2.7 

 
93.5→93.5 
0.0 
-2.51B [-3.21; -1.82] 

FPG (mmol/L) 
Baseline→End of trial 
Mean change 
Estimated difference 

 
8.9→6.1 
-2.83 

 
8.9→6.1 
-2.77 
-0.01 [-0.35; 0.33] 

  
9.7→6.2 
-3.46 

 
9.6→7.0 
-2.58 
-0.73C [-1.19; -0.27] 

Dose End of trial      



16 

Insulin (units) 
Liraglutide (mg) 
Estimated difference, 
basal insulin dose 

41 
1.5 
 
 

66D 
- 
-25.47B [-28.90; -22.05] 
 

45 
1.7 
 
 

45 
- 
-0.02 [-1.88; 1.84] 
 

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-week 
trial in patients with type 2 diabetes mellitus inadequately controlled on insulin glargine and 
metformin demonstrated a similar reduction of HbA1c in the two groups (mean value from 8.2% to 
6.7% in both groups). In both groups 66%–67% achieved HbA1c < 7%. Compared to baseline, there 
was a mean reduction in body weight of 0.9 kg for Xultophy and a mean increase of 2.6 kg for patients 
treated 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 symptomatic 
hypoglycaemia was 19.8% in the Xultophy group and 52.6% in the basal-bolus insulin group, and the 
estimated rate ratio was 0.11 [95% CI: 0.08-0.17]. The total daily insulin dose at end of trial was 
40 units for patients treated with Xultophy and 84 units (52 units of basal insulin and 32 units of bolus 
insulin) 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 were 
randomly allocated to either liraglutide (4,668) or placebo (4,672), both in addition to standards of 
care for HbA1c and cardiovascular (CV) risk factors. Primary outcome or vital status at end of trial was 
available for 99.7% and 99.6% of participants randomised to liraglutide and placebo, respectively. The 
duration of observation was minimum 3.5 years and up to a maximum of 5 years. The study 
population 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 and 
the 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 adverse 
cardiovascular events (MACE): CV death, non-fatal myocardial infarction or non-fatal stroke. 
Liraglutide was superior in preventing MACE vs placebo (Figure 6).  
 
 



17 

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

FAS: full analysis set 
CI: confidence interval  
MACE: major adverse cardiovascular event 
%: proportion in percent of subjects with an event 
N: number of subjects 

 

Favours Liraglutide Favours Placebo 
0.7 0.8 0.9 1.1 1.2 

Primary endpoint – MACE 

Components of MACE: 

 

FAS 

Cardiovascular death 

Non-fatal stroke 

Non-fatal myocardial infarction 

Expanded MACE 

Additional components in expanded MACE: 

Unstable angina pectoris (hospitalisation) 

Coronary revascularisation 

Heart failure (hospitalisation) 

Other secondary endpoints: 

All cause death 

Non-cardiovascular death 

1 

0.87 
(0.78-0.97) 

0.78  
(0.66-0.93) 

0.89  
(0.72-1.11) 

0.88 
(0.75-1.03) 

0.88  
(0.81-0.96) 

0.98 
(0.76-1.26) 

0.91 
(0.80-1.04) 

0.87 
(0.73-1.05) 

0.85 
(0.74-0.97) 

0.95 
(0.77-1.18) 

608 
(13.0) 

219 
(4.7) 
159  
(3.4) 
281  
(6.0) 
948  

(20.3) 

122 
(2.6) 
405 
(8.7) 
218 
(4.7) 

381 
(8.2) 
162 
(3.5) 

694 
(14.9) 

278  
(6.0) 
177  
(3.8) 
317  
(6.8) 
1062  
(22.7) 

124 
(2.7) 
441 
(9.4) 
248 
(5.3) 

447 
(9.6) 
169 
(3.6) 

4668 
(100) 4672 (100) 

 
 
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 addition 
to 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 2 
years 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 adverse 
cardiovascular event (MACE) defined as cardiovascular death, non-fatal myocardial infarction, or 
non-fatal stroke. The trial was designed as a non-inferiority trial to exclude a pre-specified risk margin 
of 1.3 for the hazard ratio (HR) of MACE comparing insulin degludec to insulin glargine. The 
cardiovascular 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 with 
insulin degludec and insulin glargine. 
 
 

Primary analysis (3-point MACE) 

CV Death 

Non-fatal Stroke 

Non-fatal MI 

All cause death 

0.90 (0.65-1.23) 

0.85 (0.68-1.06) 

0.91 (0.75-1.11) 

0.96 (0.76-1.21) 

0.91 (0.78-1.06) 

Hazard Ratio 
(95% CI) 

71 (1.86) 

144 (3.77) 

202 (5.29) 

136 (3.56) 

325 (8.51) 

Insulin degludec 
N (%) 

79 (2.07) 

169 (4.43) 

221 (5.79) 

142 (3.72) 

356 (9.32) 

Insulin glargine 
N (%) 

0.7 0.9 1 1.1 1.3 
Favours 

insulin degludec 
Favours 

insulin glargine 

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



18 

Figure 7 Forest plot of analysis of the composite 3-point MACE and individual cardiovascular 
endpoints in DEVOTE 
 
• Insulin secretion/beta-cell function 
Xultophy improves beta-cell function compared to insulin degludec as measured by the homeostasis 
model assessment for beta-cell function (HOMA-β). Improved insulin secretion compared to insulin 
degludec in response to a standardised meal test was demonstrated in 260 patients with type 2 diabetes 
after 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, Xultophy 
reduced mean systolic blood pressure by 1.8 mmHg compared to a reduction of 0.7 mmHg with 
insulin degludec and 2.7 mmHg with liraglutide. In patients inadequately controlled on sulfonylurea 
alone or in combination with metformin, the reduction was 3.5 mmHg with Xultophy and 3.2 mmHg 
with placebo. The differences were not statistically significant. In three trials with patients 
inadequately 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 treatment 
difference of -3.71 mmHg (p=0.0028), reduced by 3.7 mmHg with Xultophy vs 0.2 mmHg with 
insulin 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 plus 
insulin aspart, with a statistically significant estimated treatment difference of -3.70 mmHg 
(p=0.0003). 
 
Paediatric population 
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 (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Overall, the pharmacokinetics of insulin degludec and liraglutide were not affected in a clinically 
relevant manner when administered as Xultophy compared with independent injections of insulin 
degludec and liraglutide.  
 
The following reflects the pharmacokinetic properties of Xultophy unless stated that the presented data 
is from administration of insulin degludec or liraglutide alone. 
 
Absorption 
 
The overall exposure of insulin degludec was equivalent following administration of Xultophy versus 
insulin degludec alone while the Cmax was higher by 12%. The overall exposure of liraglutide was 
equivalent following administration of Xultophy versus liraglutide alone while Cmax was lower by 
23%. The differences are considered of no clinical relevance since Xultophy is initiated and titrated 
according to the individual patient’s blood glucose targets. 
 
Insulin degludec and liraglutide exposure increased proportionally with the Xultophy dose within the 
full dose range based on a population pharmacokinetic analysis. 
 
The pharmacokinetic profile of Xultophy is consistent with once-daily dosing and steady-state 
concentration of insulin degludec and liraglutide is reached after 2–3 days of daily administration. 
 
Distribution 
 
Insulin degludec and liraglutide are extensively bound to plasma proteins (>99% and >98%, 
respectively). 
 
Biotransformation 



19 

 
Insulin degludec 
Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are 
inactive. 
 
Liraglutide 
During 24 hours following administration of a single radiolabelled [3H]-liraglutide dose to healthy 
subjects, the major component in plasma was intact liraglutide. Two minor plasma metabolites were 
detected (≤9% and ≤5% of total plasma radioactivity exposure). Liraglutide is metabolised in a similar 
manner to large proteins without a specific organ having been identified as major route of elimination. 
 
Elimination 
 
The half-life of insulin degludec is approximately 25 hours and the half-life of liraglutide is 
approximately 13 hours. 
 
Special populations 
 
Elderly patients 
Age had no clinically relevant effect on the pharmacokinetics of Xultophy based on results from a 
population pharmacokinetic analysis including adult patients up to 83 years treated with Xultophy. 
 
Gender 
Gender had no clinically relevant effect on the pharmacokinetics of Xultophy based on results from a 
population pharmacokinetic analysis. 
 
Ethnic origin  
Ethnic origin had no clinically relevant effect on the pharmacokinetics of Xultophy based on results 
from a population pharmacokinetic analysis including White, Black, Indian, Asian and Hispanic 
groups. 
 
Renal impairment 
Insulin degludec 
There is no difference in the pharmacokinetics of insulin degludec between healthy subjects and 
patients with renal impairment. 
 
Liraglutide 
Liraglutide exposure was reduced in patients with renal impairment compared to individuals with 
normal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 26%, in patients with 
mild (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 trial 
including patients with type 2 diabetes with normal renal function or mild renal impairment. 
 
Hepatic impairment 
Insulin degludec 
There is no difference in the pharmacokinetics of insulin degludec between healthy subjects and 
patients with hepatic impairment. 
 
Liraglutide 
The pharmacokinetics of liraglutide was evaluated in patients with varying degrees of hepatic 
impairment in a single-dose trial. Liraglutide exposure was decreased by 13–23% in patients with mild 
to moderate hepatic impairment compared to healthy subjects. Exposure was significantly lower (44%) 
in patients with severe hepatic impairment (Child Pugh score >9). 
 
Paediatric population 



20 

No studies have been performed with Xultophy in children and adolescents below 18 years of age. 
 
5.3 Preclinical safety data 
 
The non-clinical development programme for insulin degludec/liraglutide included pivotal 
combination toxicity studies of up to 90 days duration in a single relevant species (Wistar rats) to 
support 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 toxicity 
studies. 
 
The local tissue reactions in the two studies in rabbits and pigs, respectively, were limited to mild 
inflammatory reactions. 
 
No studies have been conducted with the insulin degludec/liraglutide combination to evaluate 
carcinogenesis, mutagenesis or impairment of fertility. The following data are based upon studies with 
insulin 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 to 
human insulin. 
 
Liraglutide 
Non-clinical data reveal no special hazards for human based on conventional studies of safety 
pharmacology, repeat-dose toxicity, or genotoxicity. Non-lethal thyroid C-cell tumours were seen in 
2-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 in 
rodents are caused by a non-genotoxic, specific GLP-1 receptor-mediated mechanism to which rodents 
are particularly sensitive. The relevance for humans is likely to be low but cannot be completely 
excluded. No other treatment-related tumours have been found. 
 
Animal studies did not indicate direct harmful effects with respect to fertility but slightly increased 
early embryonic deaths at the highest dose. Dosing with liraglutide during mid-gestation caused a 
reduction in maternal weight and foetal growth with equivocal effects on ribs in rats and skeletal 
variation in the rabbit. Neonatal growth was reduced in rats while exposed to liraglutide, and persisted 
in the post-weaning period in the high dose group. It is unknown whether the reduced pup growth is 
caused by reduced pup milk intake due to a direct GLP-1 effect or reduced maternal milk production 
due to decreased caloric intake. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Glycerol 
Phenol 
Zinc acetate 
Hydrochloric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
Substances added to Xultophy may cause degradation of the active substances. 
 



21 

Xultophy must not be added to infusion fluids.  
 
This medicinal product must not be mixed with other medicinal products. 
 
6.3 Shelf life 
 
2 years. 
 
After first opening, the medicinal product can be stored for 21 days at a maximum temperature of 
30°C. The medicinal product should be discarded 21 days after first opening. 
 
6.4 Special precautions for storage 
 
Before first opening: Store in a refrigerator (2°C – 8°C). Keep away from the freezing element. Do not 
freeze. 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. 
 
6.5 Nature and contents of container  
 
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. 
 
6.6 Special precautions for disposal and other handling 
 
The pre-filled pen is designed to be used with NovoTwist or NovoFine injection needles up to a length 
of 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 patient 
should discard the needle after each injection. 
 
In the event of blocked needles, patients must follow the instructions described in the instructions for 
use accompanying the package leaflet. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
For detailed instructions for use, see the package leaflet. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 



22 

Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
8. MARKETING AUTHORISATION NUMBERS  
 
EU/1/14/947/001 
EU/1/14/947/002 
EU/1/14/947/003 
EU/1/14/947/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 18 September 2014 
Date of latest renewal: 08 July 2019 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

  

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


23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE 
SUBSTANCES AND MANUFACTURERS RESPONSIBLE FOR 
BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



24 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substances  
 
Novo Nordisk A/S 
Hallas Alle, Kalundborg, 4400, Denmark 
 
Novo Nordisk A/S 
Novo Allé, Bagsværd, 2880, Denmark 
 
Name and address of the manufacturer responsible for batch release 
 
Novo Nordisk A/S 
Novo Allé, Bagsværd, 2880, Denmark 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
• Additional risk minimisation measures 
 
The MAH shall provide educational materials prior to launch targeting all physicians and nurses who 
are expected to be involved in the treatment and management of diabetic patients and all pharmacists 
who are expected to dispense Xultophy.  
 
The MAH shall agree the final content and modality of distribution for the educational materials 
together with a communication plan, with the National Competent Authority in each Member State 
prior to distribution of the educational materials in the Member State. 
 



25 

The educational materials are aimed at increasing awareness about the fact Xultophy contains a fixed 
combination of insulin degludec and liraglutide (a GLP1-based product) and at minimising the risk of 
medication errors with Xultophy. 
 
The MAH shall ensure that healthcare professionals are informed that all patients who have been 
prescribed Xultophy should be trained on the correct use of the prefilled pen before prescribing or 
dispensing Xultophy. 
 
The educational materials should contain: 
- Summary of product characteristics and package leaflet; 
- Healthcare professional brochure that should contain the following key elements: 

• this product contains a fixed combination of insulin degludec plus 
liraglutide (a GLP1-based product) which constitutes a new treatment 
paradigm in the treatment of patients with type 2 diabetes. In this 
context, relevant precautions as reflected in the SmPC should be 
emphasised.  

• a clear explanation of the posology of the product and the meaning of 
‘dose steps’ - with reference to dose of each component for each dose 
step 

• a reminder of the need to report all medication errors irrespective of 
whether or not they resulted in an adverse event. 

  



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 

  



28 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
insulin degludec + liraglutide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
One pre-filled pen contains 300 units insulin degludec and 10.8 mg liraglutide in 3 mL solution 
1 mL solution contains 100 units of insulin degludec and 3.6 mg liraglutide 
One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide 
 
 
3. LIST OF EXCIPIENTS 
 
Glycerol, phenol, zinc acetate, hydrochloric acid and sodium hydroxide (for pH adjustment), and water 
for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
1x3 mL 
3x3 mL 
5x3 mL 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Recommended for use with NovoTwist or NovoFine disposable needles 
Needles are not included 
Read the package leaflet before use 
Subcutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNINGS, IF NECESSARY 
 
Use only clear, colourless solution 
For use by one person only 
Do not withdraw solution from the pen 
 
 
8. EXPIRY DATE 



29 

 
EXP 
After first opening: Use within 21 days 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
After first opening: Store at a maximum of 30°C or store in a refrigerator  
Keep the cap on the pen to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard the needle after each injection 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS  
 
EU/1/14/947/001 1 pre-filled pen 
EU/1/14/947/002 3 pre-filled pens 
EU/1/14/947/003 5 pre-filled pens 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xultophy 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 



30 

 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
  



31 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PEN LABEL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION 
 
Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
insulin degludec + liraglutide 
SC use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3 mL 
 
 
6. OTHER 
 
Novo Nordisk A/S 
 
 
  



32 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
MULTIPACK LABEL (with blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
insulin degludec + liraglutide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
One pre-filled pen contains 300 units insulin degludec and 10.8 mg liraglutide in 3 mL solution 
1 mL solution contains 100 units of insulin degludec and 3.6 mg liraglutide 
One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide 
 
 
3. LIST OF EXCIPIENTS 
 
Glycerol, phenol, zinc acetate, hydrochloric acid and sodium hydroxide (for pH adjustment), and water 
for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
Multipack: 10 (2 packs of 5) 3 mL pre-filled pens 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Recommended for use with NovoTwist or NovoFine disposable needles 
Needles are not included 
Read the package leaflet before use 
Subcutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNINGS, IF NECESSARY 
 
Use only clear, colourless solution 
For use by one person only 
Do not withdraw solution from the pen 
 
 
8. EXPIRY DATE 
 
EXP 



33 

After first opening: Use within 21 days 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
After first opening: Store at a maximum of 30°C or store in a refrigerator  
Keep the cap on the pen to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard the needle after each injection 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS  
 
EU/1/14/947/004 10 (2 x 5) pre-filled pens  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xultophy 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 



34 

SN: 
NN: 
 
 

  



35 

 
PARTICULARS TO APPEAR ON THE INNER PACKAGING 
 
CARTON FOR MULTIPACK (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
insulin degludec + liraglutide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCES 
 
One pre-filled pen contains 300 units insulin degludec and 10.8 mg liraglutide in 3 mL solution 
1 mL solution contains 100 units of insulin degludec and 3.6 mg liraglutide 
One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide 
 
 
3. LIST OF EXCIPIENTS 
 
Glycerol, phenol, zinc acetate, hydrochloric acid and sodium hydroxide (for pH adjustment), and water 
for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection 
 
5 pre-filled pens of 3 mL. Component of a multipack, can’t be sold separately 
 
 
5. METHOD AND ROUTE OF ADMINISTRATION 
 
Recommended for use with NovoTwist or NovoFine disposable needles 
Needles are not included 
Read the package leaflet before use 
Subcutaneous use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNINGS, IF NECESSARY 
 
Use only clear, colourless solution 
For use by one person only 
Do not withdraw solution from the pen 
 
 
8. EXPIRY DATE 
 



36 

EXP 
After first opening: Use within 21 days 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator  
Do not freeze 
After first opening: Store at a maximum of 30°C or store in a refrigerator  
Keep the cap on the pen to protect from light 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Discard the needle after each injection 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd 
Denmark 
 
 
12. MARKETING AUTHORISATION NUMBERS  
 
EU/1/14/947/004 10 (2 x 5) pre-filled pens  
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xultophy 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
 

  



37 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



38 

Package leaflet: Information for the patient 
 

Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
insulin degludec + liraglutide 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again.  
• If you have any further questions, ask your doctor, pharmacist or nurse. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Xultophy is and what it is used for  
2. What you need to know before you use Xultophy 
3. How to use Xultophy 
4. Possible side effects 
5. How to store Xultophy 
6. Contents of the pack and other information 
 
 
1. What Xultophy is and what it is used for 
 
What Xultophy is used for 
Xultophy is used to improve blood glucose (sugar) levels in adult patients with type 2 diabetes 
mellitus. You have diabetes because your body: 
• does not make enough insulin to control the level of sugar in your blood or 
• is not able to use the insulin properly. 
 
How Xultophy works  
Xultophy contains two active substances that help your body control your blood sugar:  
• insulin degludec – a long-acting basal insulin which lowers your blood sugar levels.  
• liraglutide – a ‘GLP-1 analogue’ that helps your body make more insulin during meals and 

lowers the amount of sugar made by your body.  
 
Xultophy and oral medicines for diabetes 
Xultophy is used with oral medicines for diabetes (such as metformin, pioglitazone and sulfonylurea 
medicines). It is prescribed when these medicines (used alone or with GLP-1 treatment or with basal 
insulin) are not enough to control your blood sugar levels.  
 
If you use GLP-1 treatment 
You should stop your GLP-1 treatment prior to starting on Xultophy. 
 
If you use insulin 
You should stop your insulin treatment prior to starting on Xultophy. 
 
 
2. What you need to know before you use Xultophy 
 
Do not use Xultophy 
• if you are allergic to insulin degludec or liraglutide or any of the other ingredients of this 

medicine (listed in section 6).  
 
Warnings and precautions  



39 

Talk to your doctor, pharmacist or nurse before using Xultophy.  
• If you are also taking a sulfonylurea (such as glimepiride or glibenclamide), your doctor may 

tell you to lower your sulfonylurea dose depending on your blood sugar levels. 
• Do not use Xultophy if you have type 1 diabetes mellitus or if you have ‘ketoacidosis’ (a 

condition with a build-up of acid in the blood).  
• The use of Xultophy is not recommended in patients with inflammatory bowel disease or 

delayed gastric emptying (diabetic gastroparesis). 
 
Be especially aware of the following when using Xultophy: 
• low blood sugar (hypoglycaemia) – if your blood sugar is low, follow the advice in section 4 

‘Low blood sugar (hypoglycaemia)’. 
• high blood sugar (hyperglycaemia) – if your blood sugar is high, follow the advice in section 4 

‘High blood sugar (hyperglycaemia)’. 
• Ensuring you use the right medicine – Always check the pen label before each injection to avoid 

accidentally confusing Xultophy with other products. 
 
Important things to know before you use this medicine: 
Tell your doctor if you:  
• have eye problems. Fast improvements in blood sugar control may make diabetic eye problems 

get worse for a short time. The long-term improvements in blood sugar control may ease the eye 
problems. 

• have or have had a thyroid disease.  
 
Important things to know while you are using this medicine: 
• if you have a severe stomach ache which does not go away, tell your doctor – this could be a 

sign of inflamed pancreas (acute pancreatitis).  
• dehydration (loss of fluids from the body) can happen if you are feeling or being sick (nausea or 

vomiting) or have diarrhoea – it is important to drink plenty of fluids to stop dehydration.  
 
Children and adolescents 
Do not give this medicine to children or adolescents. There is no experience with Xultophy in children 
and adolescents under 18 years old. 
 
Other medicines and Xultophy 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. Some medicines affect your blood sugar level – this may mean your Xultophy dose has to 
change. 
 
Listed below are the most common medicines, which may affect your Xultophy treatment. 
 
Your blood sugar level may fall if you take: 
• other medicines for diabetes (tablets or injections) 
• sulfonamides – for infections 
• anabolic steroids – such as testosterone 
• beta-blockers – for high blood pressure. They may make it harder to recognise the warning signs 

of low blood sugar (see section 4 ‘Warning signs of low blood sugar – these may come on 
suddenly’) 

• acetylsalicylic acid (and medicines called ‘salicylates’) – for pain and mild fever 
• monoamine oxidase (MAO) inhibitors – for depression 
• angiotensin converting enzyme (ACE) inhibitors – for some heart problems or high blood 

pressure. 
 
Your blood sugar level may rise if you take: 
• danazol – medicine affecting ovulation 
• oral contraceptives – birth control pills 
• thyroid hormones – for thyroid disease 
• growth hormone – for low levels of growth hormone  



40 

• medicines called ‘glucocorticoids’ such as cortisone – for inflammation 
• medicines called ‘sympathomimetics’ such as epinephrine (adrenaline), salbutamol or 

terbutaline – for asthma 
• water tablets called ‘thiazides’ – for high blood pressure or if your body is holding onto too 

much water (water retention). 
 
Octreotide and lanreotide – used for treatment of acromegaly (a rare illness with too much growth 
hormone). They may increase or decrease your blood sugar level. 
 
Pioglitazone – tablets used for the treatment of type 2 diabetes mellitus. Some patients with long-
standing type 2 diabetes mellitus and heart disease or previous stroke, who were treated with 
pioglitazone and insulin, experienced the development of heart failure. Inform your doctor straight 
away if you experience signs of heart failure such as unusual shortness of breath or rapid increase in 
weight or localised swelling (oedema). 
 
Warfarin or other blood thinners – medicines used to prevent clotting of the blood. Tell your doctor 
if you are taking warfarin or other blood thinners as you might need to have blood tests more often to 
measure how thick your blood is (called ‘International Normalised Ratio’ or INR test). 
 
Xultophy with alcohol 
If you drink alcohol, your need for Xultophy may change. Your blood sugar level may either rise or 
fall. You should therefore monitor your blood sugar level more often than usual. 
 
Pregnancy and breast-feeding  
Do not use Xultophy if you are pregnant or plan to become pregnant. Tell your doctor if you are 
pregnant, think you might be pregnant or are planning to have a baby. It is not known if Xultophy 
affects the baby. 
 
Do not use Xultophy if you are breast-feeding. It is not known if Xultophy passes into breast milk.  
 
Driving and using machines 
Having low or high blood sugar can affect your ability to drive or use any tools or machines. If your 
blood sugar is low or high, your ability to concentrate or react might be affected. This could be 
dangerous to yourself or others. Ask your doctor whether you can drive if: 
• you often get low blood sugar 
• you find it hard to recognise low blood sugar. 
 
Important information about some of the ingredients of Xultophy 
Xultophy contains less than 1 mmol sodium (23 mg) per dose. This means that the medicine is 
essentially ‘sodium-free’. 
 
 
3. How to use Xultophy 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor, pharmacist or 
nurse if you are not sure. 
 
If you are blind or have poor eyesight and cannot read the dose counter on the pen, do not use this pen 
without help. Get help from a person with good eyesight who is trained to use the Xultophy pre-filled 
pen. 
 
Your doctor will tell you: 
• how much Xultophy you will need each day 
• when to check your blood sugar level 
• how to adjust the dose. 
 
Your dose of Xultophy is administered as ‘dose steps’. The dose counter on the pen shows the number 



41 

of dose steps. 
 
Dosing time 
• Use Xultophy once each day, preferably at the same time every day. Choose a time of the day 

that works best for you. 
• If it is not possible to use Xultophy at the same time every day, it can be used at a different time 

of the day. Make sure to have a minimum of 8 hours between the doses. 
• You do not have to use Xultophy with a meal.  
• Always follow your doctor’s advice for dose and dose adjustment. 
• If you want to change your usual diet, check with your doctor, pharmacist or nurse first as a 

change in diet may alter your need for Xultophy. 
 
How to handle Xultophy  
Xultophy is a pre-filled dial-a-dose pen. 
• Xultophy is administered as ‘dose steps’. The dose counter on the pen shows the number of 

dose steps. 
• One dose step contains 1 unit of insulin degludec and 0.036 mg of liraglutide.  
• The maximum daily dose of Xultophy is 50 dose steps (50 units of insulin degludec and 1.8 mg 

of liraglutide). 
Carefully read the ‘Instructions on how to use’ on the other side of this leaflet and use the pen as 
described.  
Always check the pen label before you inject your medicine to ensure that you use the correct pen. 
 
How to inject 
Before you use Xultophy for the first time, your doctor or nurse will show you how to inject. 
• Xultophy is given as an injection under the skin (subcutaneously). Do not inject it into a vein or 

muscle. 
• The best places to inject are the front of your thighs, upper arms or the front of your waist 

(abdomen). 
• Change the place within the area where you inject each day to reduce the risk of developing 

lumps and skin pitting (see section 4). 
• Always use a new needle for each injection. Re-use of needles may increase the risk of blocked 

needles leading to inaccurate dosing. Dispose of the needle safely after each use. 
• Do not use a syringe to remove the solution from the pen to avoid dosing errors and potential 

overdose. 
 
Detailed instructions for use are on the other side of this leaflet. 
 
Do not use Xultophy: 
• If the pen is damaged or has not been stored correctly (see section 5). 
• If the liquid you can see through the pen window does not look clear and colourless. 
 
Use in elderly patients (65 years old or over) 
Xultophy can be used in elderly patients but if you are elderly you may need to check your blood sugar 
level more often. Talk to your doctor about changes in your dose. 
 
If you have kidney or liver problems 
If you have kidney or liver problems, you may need to check your blood sugar level more often. Talk 
to your doctor about changes in your dose. 
 
If you use more Xultophy than you should 
If you use more Xultophy than you should, your blood sugar may get low (hypoglycaemia) or you 
may feel or be sick (nausea or vomiting). If your blood sugar gets low, see the advice in section 4 
‘Low blood sugar (hypoglycaemia)’. 
 
If you forget to use Xultophy 
If you forget a dose, inject the missed dose when discovering the mistake, ensuring a minimum of 



42 

8 hours between doses. If you discover that you missed your previous dose when it is time to take your 
next regular scheduled dose, do not take a double dose. 
 
If you stop using Xultophy 
Do not stop using Xultophy without talking to your doctor. If you stop using Xultophy this could lead 
to a very high blood sugar level, see the advice in section 4 ‘High blood sugar (hyperglycaemia)’. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The 
following serious side effects may happen with this medicine: 
 
• Low blood sugar (very common: may affect more than 1 in 10 people).  

If your blood sugar level gets low you may pass out (become unconscious). Serious 
hypoglycaemia may cause brain damage and may be life-threatening. If you have signs of low 
blood sugar, take actions to increase your blood sugar level straight away. See advice in ‘Low 
blood sugar (hypoglycaemia)’ further down in this section.  

• Serious allergic reaction (anaphylactic reaction) (not known: frequency cannot be estimated 
from the available data). 

 If you have a serious allergic reaction to any of the ingredients in Xultophy, stop using 
Xultophy and see a doctor straight away. The signs of a serious allergic reaction are: 

 • local reactions spread to other parts of your body 
 • you suddenly feel unwell with sweating 
 • you have difficulty breathing 
 • you get a fast heartbeat or feel dizzy. 
 
Other side effects include: 
Common (may affect up to 1 in 10 people) 
• Lower appetite, feeling or being sick (nausea or vomiting), diarrhoea, constipation, indigestion 

(dyspepsia), inflamed lining of the stomach (gastritis), stomach ache, heartburn or bloating – 
these usually go away after a few days or weeks. 

• Injection site reactions. The signs may include bruising, bleeding, pain, redness, hives, swelling 
or itching – these usually go away after a few days. See your doctor if they do not disappear 
after a few weeks. Stop using Xultophy and see a doctor straight away if they become serious.  

• Increase of pancreatic enzymes, such as lipase and amylase. 
 
Uncommon (may affect up to 1 in 100 people) 
• Hives (red bumps on your skin that are sometimes itchy). 
• Allergic reactions (hypersensitivity) such as rash, itching and swelling of the face. 
• Dehydration (loss of fluid from the body) – it is important to drink plenty of fluids to stop 

dehydration. 
• Belching (eructation) and wind (flatulence). 
• Rash. 
• Itching. 
• Skin changes where you give the injection (‘lipodystrophy’) – the fatty tissue under the skin 

may shrink (‘lipoatrophy’) or get thicker (‘lipohypertrophy’). Changing the place where you 
inject each time may reduce the risk of these skin changes. If you notice these skin changes, tell 
your doctor or nurse. If you keep injecting in the same place, these changes can become more 
severe and affect the amount of medicine your body gets from the pen. 

• Increased heart rate. 
• Gallstones. 
• Inflamed gallbladder. 
 
Not known (frequency cannot be estimated from the available data) 



43 

• Inflamed pancreas (pancreatitis). 
• Swelling of arms or legs (peripheral oedema) – when you first start using your medicine, your 

body may keep more water than it should. This causes swelling around your ankles and other 
joints. This is usually only short-lasting. 

 
General effects from diabetes treatment 
 
► Low blood sugar (hypoglycaemia) 
 
Low blood sugar may happen if you: 
• drink alcohol 
• exercise more than usual 
• eat too little or miss a meal  
• use too much Xultophy. 
 
Warning signs of low blood sugar – these may come on suddenly 
Headache, slurred speech, fast heartbeat, cold sweat, cool pale skin, feeling sick (nausea), feeling very 
hungry, shaking, feeling nervous or worried, unusually tired, weak and sleepy or confused, difficulty 
concentrating, short-lasting changes in your sight. 
 
What to do if you get low blood sugar: 
• Eat glucose tablets or another high sugar snack – like sweets, biscuits or fruit juice (always 

carry glucose tablets or a high sugar snack, just in case). 
• Measure your blood sugar if possible and rest. You may need to measure your blood sugar more 

than once. This is because improvement in your blood sugar may not happen straight away. 
• Wait until the signs of low blood sugar have gone or when your blood sugar level has settled. 

Then carry on with your medicine as usual. 
 
What others need to do if you pass out:  
Tell everyone you spend time with that you have diabetes. Tell them what could happen if your blood 
sugar gets low, including the risk of passing out. 
 
Let them know that if you pass out, they must: 
• turn you on your side 
• get medical help straight away 
• not give you any food or drink – because you may choke. 
 
You may recover more quickly from passing out with an injection of glucagon. This can only be given 
by someone who knows how to use it. 
• If you are given glucagon, you will need sugar or a sugary snack as soon as you come round. 
• If you do not respond to a glucagon injection, you will have to be treated in a hospital. 
• If severe low blood sugar is not treated over time, it can cause brain damage. This can be short- 

or long-lasting. It may even cause death. 
 
Talk to your doctor if: 
• your blood sugar got so low that you passed out 
• you have had an injection of glucagon 
• you have had low blood sugar a few times recently. 
This is because the dosing of your Xultophy injections, food or exercise may need to be changed. 
 
► High blood sugar (hyperglycaemia) 
 
High blood sugar may happen if you: 
• drink alcohol 
• exercise less than usual 
• eat more than usual 
• get an infection or a fever 



44 

• have not used enough Xultophy, keep using less Xultophy than you need, forget to use 
Xultophy or stop using Xultophy without talking to your doctor. 

 
Warning signs of high blood sugar – these normally appear gradually 
Flushed, dry skin, feeling sleepy or tired, dry mouth, fruity (acetone) breath, urinating more often, 
feeling thirsty, losing your appetite, feeling or being sick (nausea or vomiting). 
These may be signs of a very serious condition called ‘ketoacidosis’. This is a build-up of acid in the 
blood because the body is breaking down fat instead of sugar. If not treated, this could lead to diabetic 
coma and eventually death. 
 
What to do if you get high blood sugar: 
• Test your blood sugar level. 
• Test your blood or urine for ketones. 
• Get medical help straight away. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Xultophy 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the pen label and carton after ‘EXP’. 
The expiry date refers to the last day of that month. 
 
Before opening 
Store in a refrigerator (2°C to 8°C). Keep away from the freezing element. Do not freeze. 
 
During use 
Do not freeze. You can carry Xultophy with you and keep it at room temperature (no more than 30°C) 
or in a refrigerator (2°C to 8°C) for up to 21 days. The product should be thrown away 21 days after 
first opening. 
 
Always keep the cap on the pre-filled pen when you are not using it in order to protect it from light.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Xultophy contains  
• The active substances are insulin degludec and liraglutide. Each mL of solution contains 

100 units of insulin degludec and 3.6 mg liraglutide. Each unused pre-filled pen (3 mL) contains 
300 units of insulin degludec and 10.8 mg liraglutide. 

• The other ingredients are glycerol, phenol, zinc acetate, hydrochloric acid and sodium 
hydroxide (for pH adjustment), and water for injections. See also section 2 ‘Important 
information about some of the ingredients of Xultophy’ for information on sodium. 

 
What Xultophy looks like and contents of the pack 
Xultophy is a clear and colourless solution. 
Pack sizes of 1, 3, 5 and a multipack containing 10 (2 packs of 5) pens of 3 mL. Not all pack sizes may 
be marketed. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


45 

 
Marketing Authorisation Holder and Manufacturer 
Novo Nordisk A/S 
Novo Allé 
DK-2880 Bagsværd, Denmark 
 
Now turn over for information on how to use your pre-filled pen. 
 
This leaflet was last revised in  
 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 

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


46 

Instructions on how to use Xultophy 100 units/mL + 3.6 mg/mL solution for injection 
 

 
Please read these instructions carefully before using your Xultophy pre-
filled pen. 
Do not use the pen without proper training from your doctor or nurse. 
Start by checking your pen to make sure that it contains Xultophy 
100 units/mL + 3.6 mg/mL, then look at the illustrations below to get to know 
the different parts of your pen and needle. 
 
If you are blind or have poor eyesight and cannot read the dose counter 
on the pen, do not use this pen without help. Get help from a person with 
good eyesight who is trained to use the Xultophy pre-filled pen. 
 
Xultophy is a medicine that contains insulin degludec and liraglutide. 
Xultophy is administered as ‘dose steps’. One dose step contains 1 unit 
insulin degludec + 0.036 mg liraglutide. 
 
Your pen is a pre-filled dial-a-dose pen. It contains 3 mL of Xultophy solution. 
It delivers doses from:  
– 1 dose step  
– to a maximum of 50 dose steps (50 units insulin degludec + 1.8 mg 

liraglutide) 
 

Your pen delivers doses in increments of 1 dose step.  
Do not do any conversion of your dose. The dose steps dialled equal the 
number shown in the dose counter.  
 
Your pen is designed to be used with NovoTwist or NovoFine disposable 
needles up to a length of 8 mm and as thin as 32G. Needles are not included in 
the pack. 
 

 Important information 
Pay special attention to these notes as they are important for safe use of the 
pen. 

 



47 

 
Xultophy pre-filled pen and 
needle (example) 

Pen cap Outer  
needle cap 

Inner 
needle cap 

Needle 

Paper tab 

Pen scale 

Pen window 

Pen label 

Dose counter 
Dose pointer 

Dose 
button 
with 
smooth 
surface 

Dose 
selector 
Dose 
button 

 

 

1 Prepare your pen with a new needle 
 
• Check the name and coloured label of your pen, to make sure that it 

contains Xultophy. 
This is especially important if you take more than one type of injectable 
medicine. Taking the wrong medicine could be harmful to your health. 

• Pull off the pen cap. 

 A 

 



48 

• Check that the solution in your pen is clear and colourless. Look 
through the pen window. If the solution looks cloudy, do not use the 
pen. 

 B 

 

• Take a new needle, and tear off the paper tab. 
 

 C 

 

• Push the needle straight onto the pen. Turn until it is on tight.  D 

 

• Pull off the outer needle cap and keep it for later. You will need it 
after the injection, to safely remove the needle from the pen. 

 

 E 

 

• Pull off the inner needle cap and throw it away. If you try to put it 
back on, you may accidentally stick yourself with the needle.  
A drop of solution may appear at the needle tip. This is normal, but you 
must still check the flow. 
Do not attach a new needle to your pen until you are ready to take your 
injection. 

 
 Always use a new needle for each injection. 

This may prevent blocked needles, contamination, infection and 
inaccurate dosing. 

 Never use a bent or damaged needle. 

 F 

 
 

2 Check the flow 
 
• Turn the dose selector to select 2 dose steps. Make sure the dose 

counter shows 2. 
• The dose counter and the dose pointer show how many dose steps of 

Xultophy you select. 
 

 A 

2  
dose steps 

selected 
 



49 

• Hold the pen with the needle pointing up.  
Tap the top of the pen gently a few times to let any air bubbles rise to 
the top. 

 B 

 

• Press and hold in the dose button until the dose counter returns to 0. 
The 0 must line up with the dose pointer. 
A drop of solution should appear at the needle tip. 

 
A small drop may remain at the needle tip, but it will not be injected. 
If no drop appears, repeat steps 2A to 2C up to 6 times. If there is still 
no drop, change the needle and repeat steps 2A to 2C once more. 
If a drop of solution still does not appear, dispose of the pen and use a 
new one. 

 
 Always make sure that a drop appears at the needle tip before you 

inject. This makes sure that the solution flows. 
If no drop appears, you will not inject any medicine, even though the 
dose counter may move. This may indicate a blocked or damaged 
needle. 

 
 It is important always to check the flow before you inject. If you do 

not check the flow, you may get too little medicine, or no medicine at 
all. This may lead to high blood sugar level. 

 

 C 

 
 

3 Select your dose 
 
• Turn the dose selector to select the dose you need. 

The dose counter shows the dose in dose steps. 
If you select a wrong dose, you can turn the dose selector forward or 
backward to the correct dose. 
The pen can dial up to a maximum of 50 dose steps. 
The dose selector changes the number of dose steps. 
Only the dose counter and dose pointer will show how many dose steps 
you select per dose. 
You can select up to 50 dose steps per dose. When your pen contains 
less than 50 dose steps, the dose counter stops at the number of dose 
steps left. 
The dose selector clicks differently when turned forward, backward or 
past the number of dose steps left. Do not count the pen clicks. 

 
 Always use the dose counter and the dose pointer to see how many 

dose steps you have selected before injecting the medicine. 
Do not count the pen clicks. If you select and inject the wrong dose, 
your blood sugar level may get high or low. 
Do not use the pen scale, it only shows approximately how much 
solution is left in your pen. 
 

 A 

Examples 

5 
dose steps 

selected 

24  
dose steps 

selected 
 

 



50 

How much solution is left? 
 
• The pen scale shows you approximately how much solution is left in 

your pen. 

 A 

Approx. 
how much 
solution is 

left 
 

• To see precisely how much solution is left, use the dose counter: 
Turn the dose selector until the dose counter stops. 
If it shows 50, at least 50 dose steps are left in your pen. If it shows less 
than 50, the number shown is the number of dose steps left in your pen. 
 

• If you need more medicine than what is left in your pen, you can split 
your dose between two pens. 
 

 Be very careful to calculate correctly if splitting your dose.  
If in doubt, take the full dose with a new pen. If you split the dose 
wrongly, you will inject too little or too much medicine. This may make 
your blood sugar level high or low. 

 

 B 

Example 

Dose 
counter 

stopped: 42 
dose steps 

left  

4 Inject your dose 
 
• Insert the needle into your skin as your doctor or nurse has shown 

you. 
• Make sure you can see the dose counter. Do not cover it with your 

fingers. This could interrupt the injection. 

 A 

 

• Press and hold down the dose button until the dose counter shows 0. 
The 0 must line up with the dose pointer. You may then hear or feel a 
click. 

 B 

 

• Keep the needle in your skin after the dose counter has returned to 0 
and count slowly to 6. 

• If the needle is removed earlier, you may see a stream of solution 
coming from the needle tip. If so, the full dose will not be delivered, and 
you should increase the frequency of checking your blood sugar level. 

 C Count slowly: 

1-2-3-4-5-6 

 



51 

• Remove the needle from your skin. 
If blood appears at the injection site, press lightly. Do not rub the area. 
 
You may see a drop of solution at the needle tip after injecting. This is 
normal and does not affect your dose. 
 

 Always watch the dose counter to know how many dose steps you 
inject. Hold the dose button down until the dose counter shows 0. If the 
dose counter does not return to 0, the full dose has not been delivered, 
which may lead to high blood sugar level. 
 
How to identify a blocked or damaged needle? 
• If 0 does not appear in the dose counter after continuously 

pressing the dose button, you may have used a blocked or 
damaged needle. 

• In this case - you have not received any medicine - even though 
the dose counter has moved from the original dose that you have 
set. 

How to handle a blocked needle? 
Change the needle as described in section 5 and repeat all steps starting 
with section 1: Prepare your pen with a new needle. Make sure you 
select the full dose you need. 
Never touch the dose counter when you inject. This can interrupt the 
injection. 

 

 D 

 
 

5 After your injection 
 
• Lead the needle tip into the outer needle cap on a flat surface without 

touching the needle or the outer cap. 
 

 A 

 

• Once the needle is covered, carefully push the outer needle cap 
completely on. 

• Unscrew the needle and dispose of it carefully as instructed by your 
doctor or nurse. 

 B 

 

• Put the pen cap on your pen after each use to protect the solution from 
light. 
 
Always dispose of the needle after each injection to ensure the use of 
a sharp needle and prevent blocked needles. If the needle is blocked, 
you will not inject any medicine. 
When the pen is empty, throw it away without a needle on as instructed 
by your doctor, nurse, pharmacist or local authorities. 
 

 Never try to put the inner needle cap back on the needle. You may 
stick yourself with the needle. 

 Always remove the needle from your pen after each injection. 
This may prevent blocked needles, contamination, infection, leakage of 
solution and inaccurate dosing. 

 C 

 
 



52 

 Further important information 
 
• Always keep an extra pen and new needles, in case of loss or damage. 
• Always keep your pen and needles out of sight and reach of others, 

especially children. 
• Never share your pen with other people. Your medicine might be 

harmful to their health. 
• Never share your needles with other people. It might lead to cross-

infection. 
• Caregivers must be very careful when handling used needles – to 

prevent needle injury and cross-infection. 
 

 

Caring for your pen 
 
• Do not leave the pen in a car or other place where it can get too hot or 

too cold. 
• Do not store your pen at temperatures above 30°C. 
• Do not expose your pen to dust, dirt or liquid. 
• Do not wash, soak or lubricate your pen. If necessary, clean it with 

mild detergent on a moistened cloth. 
• Do not drop your pen or knock it against hard surfaces.  
 If you drop it or suspect a problem, attach a new needle and check the 

flow before you inject. 
• Do not try to refill your pen. Once empty, it must be disposed of. 
• Do not try to repair your pen or pull it apart. 

 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET