VICTOZA 6mg / ml injection for pre-filled pen medication leaflet

Victoza 6 mg/ml solution for injection in pre-filled pen

1 ml of solution contains 6 mg of liraglutide*. One pre-filled pen contains 18 mg liraglutide in 3 ml.

* human glucagon-like peptide-1 (GLP-1) analogue produced by recombinant DNA technology in

Saccharomyces cerevisiae.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear and colourless or almost colourless, isotonic solution; pH=8.15.

Victoza is indicated for the treatment of adults, adolescents and children aged 10 years and above withinsufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise

* as monotherapy when metformin is considered inappropriate due to intolerance orcontraindications

* in addition to other medicinal products for the treatment of diabetes.

For study results with respect to combinations, effects on glycaemic control and cardiovascular events,and the populations studied, see sections 4.4, 4.5 and 5.1.

To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least oneweek, the dose should be increased to 1.2 mg. Some patients are expected to benefit from an increasein dose from 1.2 mg to 1.8 mg and based on clinical response, after at least one week, the dose can beincreased to 1.8 mg to further improve glycaemic control. Daily doses higher than 1.8 mg are notrecommended.

When Victoza is added to a sulfonylurea or insulin, a reduction in the dose of sulfonylurea or insulinshould be considered to reduce the risk of hypoglycaemia (see section 4.4). Combination therapy withsulfonylurea is only valid for adult patients.

Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza. Blood glucoseself-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Victozatherapy is started and insulin is reduced. A stepwise approach to insulin dose reduction isrecommended.

Elderly patients (>65 years old)

No dose adjustment is required based on age (see section 5.2).

No dose adjustment is required for patients with mild, moderate or severe renal impairment. There isno therapeutic experience in patients with end-stage renal disease, and Victoza is therefore notrecommended for use in these patients (see sections 5.1 and 5.2).

No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Victozais not recommended for use in patients with severe hepatic impairment (see section 5.2).

No dose adjustment is required for adolescents and children aged 10 years and above. No data areavailable for children below 10 years of age (see sections 5.1 and 5.2).

Victoza must not be administered intravenously or intramuscularly.

Victoza is administered once daily at any time, independent of meals, and can be injectedsubcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can bechanged without dose adjustment. However, it is preferable that Victoza is injected around the sametime of the day, when the most convenient time of the day has been chosen. Injection sites shouldalways be rotated in order to reduce the risk of injection site amyloid deposits (see section and 4.8).

For further instructions on administration, see section 6.6.

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

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

Liraglutide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependentpatients after rapid discontinuation or dose reduction of insulin (see section 4.2).

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

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

There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis.

Use of liraglutide is not recommended in these patients since it is associated with transientgastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should beinformed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, liraglutideshould be discontinued; if acute pancreatitis is confirmed, liraglutide should not be restarted (seesections 4.8 and 5.1).

Thyroid adverse events, such as goitre, have been reported in clinical trials and in particular in patientswith pre-existing thyroid disease. Liraglutide should therefore be used with caution in these patients.

Patients receiving liraglutide in combination with a sulfonylurea or insulin may have an increased riskof hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by a reduction in thedose of sulfonylurea or insulin.

Signs and symptoms of dehydration, including renal impairment and acute renal failure, have beenreported in patients treated with liraglutide. Patients treated with liraglutide should be advised of thepotential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoidfluid depletion.

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

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

In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions withother active substances related to cytochrome P450 and plasma protein binding.

The small delay of gastric emptying with liraglutide may influence absorption of concomitantlyadministered oral medicinal products. Interaction studies did not show any clinically relevant delay ofabsorption and therefore no dose adjustment is required. Few patients treated with liraglutide reportedat least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oralmedicinal products.

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

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1000 mg.

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

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

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

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

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

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

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

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

Insulin

No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and insulindetemir when administering a single dose of insulin detemir 0.5 U/kg with liraglutide 1.8 mg at steadystate in patients with type 2 diabetes.

Interaction studies have only been performed in adults.

There are no adequate data from the use of liraglutide in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Liraglutide should not be used during pregnancy, and the use of insulin is recommended instead. If apatient wishes to become pregnant, or pregnancy occurs, treatment with Victoza should bediscontinued.

It is not known whether liraglutide is excreted in human milk. Animal studies have shown that thetransfer of liraglutide and metabolites of close structural relationship into milk is low. Non-clinicalstudies have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section5.3). Because of lack of experience, Victoza should not be used during breast-feeding.

Apart from a slight decrease in the number of live implants, animal studies did not indicate harmfuleffects with respect to fertility.

Victoza has no or negligible influence on the ability to drive and use machines.

Patients should be advised to take precautions to avoid hypoglycaemia while driving and usingmachines, in particular when Victoza is used in combination with a sulfonylurea or insulin.

In five large long-term clinical phase 3a trials over 2,500 adult patients have received treatment with

Victoza alone or in combination with metformin, a sulfonylurea (with or without metformin) ormetformin plus rosiglitazone.

The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders:nausea and diarrhoea were very common, whereas vomiting, constipation, abdominal pain, anddyspepsia were common. At the beginning of the therapy, these gastrointestinal adverse reactions mayoccur more frequently. These reactions usually diminish within a few days or weeks on continuedtreatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia wascommon, and very common when liraglutide is used in combination with a sulfonylurea. Severehypoglycaemia has primarily been observed when combined with a sulfonylurea.

Table 1 lists adverse reactions reported in long-term phase 3a controlled trials, the LEADER trial (along-term cardiovascular outcome trial) and spontaneous (post-marketing) reports. Frequencies for allevents have been calculated based on their incidence in phase 3a clinical trials.

Frequencies are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1 Adverse reactions from long-term controlled phase 3a trials, the long-termcardiovascular outcome trial (LEADER) and spontaneous (post-marketing) reports

MedDRAsystem Veryorgan common Common Uncommon Rare Very rare Not knownclasses

Infections Nasopharyngitisand Bronchitisinfestations

Immune Anaphylactisystem c reactionsdisorders

Metabolism Hypoglycaemia Dehydratioand nutrition Anorexia ndisorders Appetitedecreased

Nervous Headache Dysgeusiasystem Dizzinessdisorders

MedDRAsystem Very Common Uncommon Rare Very rare Not knownorgan commonclasses

Cardiac Increased heartdisorders rate

Gastrointesti Nausea Vomiting Delayed Intestinal Pancreatitisnal disorders Diarrhoea Dyspepsia gastric obstruction (including

Abdominal pain emptying necrotisingupper pancreatitis)

Gastritis

Flatulence

Abdominaldistension

Gastroesophageal reflux disease

Abdominaldiscomfort

Toothache

Hepatobiliar Cholelithiasy disorders is

Cholecystitis

Skin and Rash Urticaria Cutaneoussubcutaneou Pruritus amyloidosiss tissuedisorder

Renal and Renalurinary impairmentdisorders Renalfailure acute

General Fatigue Malaisedisorders and Injection siteadministratio reactionsn siteconditions

Investigation Increaseds lipase*

Increasedamylase*

* From controlled phase 3b and 4 clinical trials only where they were measured.

In a clinical trial with liraglutide as monotherapy, rates of hypoglycaemia reported with liraglutidewere lower than rates reported for patients treated with active comparator (glimepiride). The mostfrequently reported adverse reactions were gastrointestinal disorders, infections and infestations.

Most episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of severehypoglycaemia were observed in the trial with liraglutide used as monotherapy. Severe hypoglycaemiamay occur uncommonly and has primarily been observed when liraglutide is combined with asulfonylurea (0.02 events/patient year). Very few episodes (0.001 events/patient year) were observedwith administration of liraglutide in combination with oral antidiabetics other than sulfonylureas. Therisk of hypoglycaemia is low with combined use of basal insulin and liraglutide (1.0 events per patientyear, see section 5.1). In the LEADER trial, severe hypoglycaemic episodes were reported at a lowerrate with liraglutide vs placebo (1.0 vs 1.5 events per 100 patient years; estimated rate ratio 0.69 [0.51to 0.93]) (see section 5.1). For patients treated with premix insulin at baseline and at least for thefollowing 26 weeks, the rate of severe hypoglycaemia for both liraglutide and placebo was 2.2 eventsper 100 patient years.

When combining liraglutide with metformin, 20.7% of patients reported at least one episode ofnausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining liraglutidewith a sulfonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patientsreported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in adose-dependent fashion. With continued therapy, the frequency and severity decreased in mostpatients who initially experienced nausea.

Patients >70 years may experience more gastrointestinal effects when treated with liraglutide.

Patients with mild and moderate renal impairment (creatinine clearance 60-90 ml/min and 30-59 ml/min, respectively) may experience more gastrointestinal effects when treated with liraglutide.

Few cases of cholelithiasis (0.4%) and cholecystitis (0.1%) have been reported during long-term,controlled phase 3a clinical trials with liraglutide. In the LEADER trial, the frequency of cholelithiasisand cholecystitis was 1.5% and 1.1% for liraglutide and 1.1% and 0.7% for placebo, respectively (seesection 5.1).

Cutaneous amyloidosis

Cutaneous amyloidosis may occur at the injection site (See section 4.2)”

The incidence of withdrawal due to adverse reactions was 7.8% for liraglutide-treated patients and3.4% for comparator-treated patients in the long-term controlled trials (26 weeks or longer). The mostfrequent adverse reactions leading to withdrawal for liraglutide-treated patients were nausea (2.8% ofpatients) and vomiting (1.5%).

Injection site reactions have been reported in approximately 2% of patients receiving Victoza in long-term (26 weeks or longer) controlled trials. These reactions have usually been mild.

Few cases of acute pancreatitis (<0.2%) have been reported during long-term, controlled phase 3clinical trials with Victoza. Pancreatitis was also reported from marketed use. In the LEADER trial,the frequency of acute pancreatitis confirmed by adjudication was 0.4% for liraglutide and 0.5% forplacebo, respectively (see sections 4.4 and 5.1).

Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of

Victoza.

Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations,dyspnoea and oedema have been reported with marketed use of Victoza. Few cases (0.05%) ofangioedema have been reported during all long-term clinical trials with Victoza.

Overall, frequency, type and severity of adverse reactions in adolescents and children aged 10 yearsand above were comparable to that observed in the adult population. Rate of confirmedhypoglycaemic episodes was higher with liraglutide (0.58 events/patient year) compared to placebo(0.29 events/patient year). In patients treated with insulin prior to a confirmed hypoglycaemic episodethe rate was higher with liraglutide (1.82 events/patient year) compared to placebo (0.91 events/patientyears). No severe hypoglycaemic episodes occurred in the liraglutide treatment group.

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

From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) therecommended maintenance dose. Events reported included severe nausea, vomiting, diarrhoea andsevere hypoglycaemia.

In the event of overdose, appropriate supportive treatment should be initiated according to thepatient’s clinical signs and symptoms. The patient should be observed for clinical signs of dehydrationand blood glucose should be monitored.

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues. ATCcode: A10BJ02

Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to andactivates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenousincretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells.

Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humanssuitable for once daily administration. Following subcutaneous administration, the protracted actionprofile is based on three mechanisms: self-association, which results in slow absorption; binding toalbumin; and higher enzymatic stability towards the dipeptidyl peptidase -4 (DPP-4) and neutralendopeptidase (NEP) enzymes, resulting in a long plasma half-life.

Liraglutide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase incyclic adenosine monophosphate (cAMP). Liraglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also ina glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated andglucagon secretion is inhibited. Conversely, during hypoglycaemia liraglutide diminishes insulinsecretion and does not impair glucagon secretion. The mechanism of blood glucose lowering alsoinvolves a minor delay in gastric emptying. Liraglutide reduces body weight and body fat massthrough mechanisms involving reduced hunger and lowered energy intake, GLP-1 is a physiologicalregulator 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 regionsinvolved in regulation of appetite, where liraglutide via specific activation of the GLP-1 receptor(GLP-1R) increased key satiety and decreased key hunger signals, thereby leading to lower bodyweight.

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

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

Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting andpostprandial blood glucose in patients with type 2 diabetes mellitus.

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality arean integral part of the treatment of type 2 diabetes.

Five double-blind, randomised, controlled clinical phase 3a adult trials were conducted to evaluate theeffects of liraglutide on glycaemic control (Table 2). Treatment with liraglutide produced clinicallyand statistically significant improvements in glycosylated haemoglobin A1c (HbA1c), fasting plasmaglucose and postprandial glucose compared with placebo.

These trials included 3,978 exposed patients with type 2 diabetes mellitus (2,501 patients treated withliraglutide), 53.7% men and 46.3% women, 797 patients (508 treated with liraglutide) were ≥65 yearsof age and 113 patients (66 treated with liraglutide) were ≥75 years of age.

Additional trials were conducted with liraglutide that included 1,901 patients in four unblinded,randomised, controlled clinical trials (including 464, 658, 323 and 177 patients per trial) and onedouble-blind, randomised, controlled clinical trial in patients with type 2 diabetes mellitus andmoderate renal impairment (279 patients).

A large cardiovascular outcomes trial (the LEADER trial) was also conducted with liraglutide in 9,340patients with type 2 diabetes mellitus at high cardiovascular risk.

* Glycaemic control

Liraglutide monotherapy for 52 weeks resulted in statistically significant and sustained reductions in

HbA1c compared with glimepiride 8 mg (-0.84% for 1.2 mg, -1.14% for 1.8 mg vs -0.51% forcomparator) in patients previously treated with either diet and exercise or OAD monotherapy at nomore than half-maximal dose (Table 2).

Combination with oral antidiabetics

Liraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin androsiglitazone or SGLT2i ± metformin resulted in statistically significant and sustained reductions in

HbA1c compared with patients receiving placebo (Table 2).

Table 2 Liraglutide clinical phase 3 trials in monotherapy (52 weeks) and in combinationwith oral antidiabetics (26 weeks)

N Mean Mean HbA1c Patients (%) Mean Meanbaseline change from achieving baseline weight

HbA1c (%) baseline (%) HbA1c<7% weight (kg) change frombaseline(kg)

Liraglutide 1.2 mg 251 8.18 -0.84* 42.81, 58.33 92.1 -2.05**

Liraglutide 1.8 mg 246 8.19 -1.14** 50.91, 62.03 92.6 -2.45**

Glimepiride 8 mg/day 248 8.23 -0.51 27.81, 30.83 93.3 1.12

Add-on to metformin (2,000 mg/day)

Liraglutide 1.2 mg 240 8.3 -0.97† 35.31, 52.82 88.5 -2.58**

Liraglutide 1.8 mg 242 8.4 -1.00† 42.41, 66.32 88.0 -2.79**

Placebo 121 8.4 0.09 10.81, 22.52 91.0 -1.51

Glimepiride 4 mg/day 242 8.4 -0.98 36.31, 56.02 89.0 0.95

Add-on to glimepiride (4 mg/day)

Liraglutide 1.2 mg 228 8.5 -1.08** 34.51, 57.42 80.0 0.32**

N Mean Mean HbA1c Patients (%) Mean Meanbaseline change from achieving baseline weight

HbA1c (%) baseline (%) HbA1c<7% weight (kg) change frombaseline(kg)

Liraglutide 1.8 mg 234 8.5 -1.13** 41.61, 55.92 83.0 -0.23**

Placebo 114 8.4 0.23 7.51, 11.82 81.9 -0.10

Rosiglitazone 4 231 8.4 -0.44 21.91, 36.12 80.6 2.11mg/day

Add-on to metformin (2,000 mg/day) + rosiglitazone (4 mg twice daily)

Liraglutide 1.2 mg 177 8.48 -1.48 57.51 95.3 -1.02

Liraglutide 1.8 mg 178 8.56 -1.48 53.71 94.9 -2.02

Placebo 175 8.42 -0.54 28.11 98.5 0.60

Add-on to metformin (2,000 mg/day) + glimepiride (4 mg/day)

Liraglutide 1.8 mg 230 8.3 -1.33* 53.11 85.8 -1.81**

Placebo 114 8.3 -0.24 15.31 85.4 -0.42

Insulin glargine4 232 8.1 -1.09 45.81 85.2 1.62

Add-on to SGLT2i5 ± metformin (≥1500 mg/day)

Liraglutide 1.8 mg 203 8.00 -1.02*** 54.8*** 91.0 -2.92

Placebo 100 7.96 -0.28 13.9 91.4 -2.06

*Superiority (p<0.01) vs active comparator; **Superiority (p<0.0001) vs active comparator; ***Superiority(p<0.001) vs active comparator, †Non-inferiority (p<0.0001) vs active comparator1all patients; 2previous OAD monotherapy; 3previous diet treated patients5Victoza add-on to SGLT2i was investigated at all approved doses of SGLT2i4the dosing of insulin glargine was open-labelled and was applied according to Guideline for titration of insulinglargine. Titration of the insulin glargine dose was managed by the patient after instruction by the investigator:

Guideline for titration of insulin glargine

Self-measured FPG Increase in insulin glargine dose (IU)≤5.5 mmol/l (≤100 mg/dl) Target No adjustment>5.5 and <6.7 mmol/l (>100 and <120 mg/dl) 0-2 IUa≥6.7 mmol/l (≥120 mg/dl) 2 IUa According to the individualised recommendation by the investigator at the previous visit, for exampledepending on whether the patient has experienced hypoglycaemia.

Combination with insulin

In a 104-week clinical trial, 57% of patients with type 2 diabetes treated with insulin degludec incombination with metformin achieved a target HbA1c <7% and the remaining patients continued in a26-week open label trial and were randomised to add liraglutide or a single dose of insulin aspart (withthe largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% inorder to minimize the risk of hypoglycaemia. Addition of liraglutide resulted in a statisticallysignificantly greater reduction of HbA1c (-0.73% for liraglutide vs -0.40% for comparator) and bodyweight (-3.03 vs 0.72 kg). The rate of hypoglycaemic episodes (per patient year of exposure) wasstatistically significantly lower when adding liraglutide compared to adding a single dose of insulinaspart (1.0 vs 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21).

In a 52-week clinical trial, the addition of insulin detemir to liraglutide 1.8 mg and metformin inpatients not achieving glycaemic targets on liraglutide and metformin alone resulted in a HbA1cdecrease from baseline of 0.54%, compared to 0.20% in the liraglutide 1.8 mg and metformin controlgroup. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemicepisodes (0.23 versus 0.03 events per patient years).

In the LEADER trial, (see subsection Cardiovascular evaluation), 873 patients were on premix insulin(with or without OAD(s)) at baseline and at least for the following 26 weeks. The mean HbA1c atbaseline was 8.7% for liraglutide and placebo. At week 26, the estimated mean change in HbA1cwas -1.4% and -0.5% for liraglutide and placebo, respectively, with an estimated treatment differenceof -0.9 [-1.00; -0.70]95% CI. The safety profile of liraglutide in combination with premix insulin wasoverall comparable to that observed for placebo in combination with premix insulin (see section 4.8).

Use in patients with renal impairment

In a double-blind trial comparing the efficacy and safety of liraglutide 1.8 mg versus placebo as add-on to insulin and/or OAD in patients with type 2 diabetes and moderate renal impairment, liraglutidewas superior to placebo treatment in reducing HbA1c after 26 weeks (-1.05% vs -0.38%). Significantlymore patients achieved HbA1c below 7% with liraglutide compared with placebo (52.8% vs 19.5%). Inboth groups a decrease in body weight was seen: -2.4 kg with liraglutide vs -1.09 kg with placebo.

There was a comparable risk of hypoglycaemic episodes between the two treatment groups. The safetyprofile of liraglutide was generally similar to that observed in other studies with liraglutide.

* Proportion of patients achieving reductions in HbA1c

Liraglutide alone resulted in a statistically significant greater proportion of patients achieving HbA1c≤6.5% at 52 weeks compared with patients receiving glimepiride (37.6% for 1.8 mg and 28.0% for1.2 mg vs 16.2% for comparator).

Liraglutide in combination with metformin, glimepiride, metformin and rosiglitazone or SGLT2i ±metformin resulted in a statistically significant greater proportion of patients achieving an HbA1c≤6.5% at 26 weeks compared with patients receiving these agents alone.

* Fasting plasma glucose

Treatment with liraglutide alone and in combination with one or two oral antidiabetic drugs resulted ina reduction in fasting plasma glucose of 13-43.5 mg/dl (0.72-2.42 mmol/l). This reduction wasobserved within the first two weeks of treatment.

* Postprandial glucose

Liraglutide reduced postprandial glucose across all three daily meals by 31-49 mg/dl (1.68-2.71 mmol/l).

* Beta-cell function

Clinical trials with liraglutide indicate improved beta-cell function based on measures such as thehomeostasis model assessment for beta-cell function (HOMA-B) and the proinsulin to insulin ratio.

Improved first and second phase insulin secretion after 52 weeks treatment with liraglutide wasdemonstrated in a subset of patients with type 2 diabetes (n=29).

* Body weight

Treatment with liraglutide in combination with metformin, metformin and glimepiride, metformin androsiglitazone or SGLT2i with or without metformin was associated with a sustained weight reductionin the range from 0.86 kg to 2.62 kg compared with placebo.

Larger weight reduction was observed with increasing body mass index (BMI) at baseline.

* Cardiovascular evaluation

Post-hoc analysis of serious major adverse cardiovascular events (cardiovascular death, myocardialinfarction, stroke) from all intermediate and long-term phase 2 and 3 trials (ranging from 26 and up to100 weeks duration) including 5,607 patients (3,651 exposed to liraglutide), showed no increase incardiovascular risk (incidence ratio of 0.75 (95% CI 0.35; 1.63)) for liraglutide versus all comparators.

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

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

Liraglutide was superior in preventing MACE vs placebo (Figure 1). The estimated hazard ratio wasconsistently below 1 for all 3 MACE components.

Liraglutide also significantly reduced the risk of expanded MACE (primary MACE, unstable anginapectoris leading to hospitalisation, coronary revascularisation, or hospitalisation due to heart failure)and other secondary endpoints (Figure 2).

Placebo

Victoza

HR: 0.8795% CI [0.78; 0.97]p<0.001 for non-inferiorityp=0.005 for superiority

Time from randomisation (months)

Patients at risk

Placebo 4672 4587 4473 4352 4237 4123 4010 3914 1543 407

Victoza 4668 4593 4496 4400 4280 4172 4072 3982 1562 424

FAS: full analysis set.

Figure 1: Kaplan Meier plot of time to first MACE - FAS population

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

FAS 4668 4672(100) (100)

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

Components of MACE:

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

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

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

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

Additional components in expanded MACE:

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

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

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

Other secondary endpoints:

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

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

FAS: full analysis set

CI: confidence interval 0.7 0.8 0.9 1 1.1 1.2

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

N: number of subjects

Figure 2: Forest plot of analyses of individual cardiovascular event types - FAS population

A significant and sustained reduction in HbA1c from baseline to month 36 was observed withliraglutide vs placebo, in addition to standard of care (-1.16% vs -0.77%; estimated treatmentdifference [ETD] -0.40% [-0.45; -0.34]). The need for treatment intensification with insulin wasreduced by 48% with liraglutide vs placebo in insulin-naive patients at baseline (HR 0.52 [0.48;0.57]).

Patients with an event (%)

* Blood pressure and heart rate

Over the duration of the phase 3a trials, liraglutide decreased the systolic blood pressure on average of2.3 to 6.7 mmHg from baseline and compared to active comparator the decrease was 1.9 to 4.5 mmHg.

A mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed withliraglutide in long-term clinical trials including LEADER. In the LEADER trial, no long-term clinicalimpact of increased heart rate on the risk of cardiovascular events was observed.

* Microvascular evaluation

In the LEADER trial, microvascular events comprised nephropathy and retinopathy outcomes. Theanalysis of time to first microvascular event for liraglutide vs placebo had a HR of 0.84 [0.73, 0.97].

The HR for liraglutide vs placebo was 0.78 [0.67, 0.92] for time to first nephropathy event and 1.15[0.87, 1.52] for time to first retinopathy event.

* Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing proteins orpeptides, patients may develop anti-liraglutide antibodies following treatment with liraglutide. Onaverage, 8.6% of patients developed antibodies. Antibody formation has not been associated withreduced efficacy of liraglutide.

In a double-blind study comparing the efficacy and safety of Victoza 1.8 mg versus placebo as add-onto metformin ± insulin in adolescents and children aged 10 years and above with type 2 diabetes,

Victoza was superior to placebo treatment in reducing HbA1c after 26 weeks (-1.06, [-1.65, 0.46]). Thetreatment difference in HbA1c was 1.3% after additional 26 weeks of open label extension, confirmingthe sustained glycaemic control with Victoza.

The efficacy and safety profile of Victoza was comparable to that observed in the adult populationtreated with Victoza. Based on adequate glycaemic control or tolerability, 30% of trial subjectsremained on a dose of 0.6 mg, 17% escalated to a dose of 1.2 mg and 53% escalated to a dose of1.8 mg.

Other clinical data

In an open label trial comparing the efficacy and safety of liraglutide (1.2 mg and 1.8 mg) andsitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy(mean HbA1c 8.5%), liraglutide at both doses was statistically superior to sitagliptin treatment inreducing HbA1c after 26 weeks (-1.24%, -1.50% vs -0.90%, p<0.0001). Patients treated withliraglutide had a significant decrease in body weight compared to that of patients treated withsitagliptin (-2.9 kg and -3.4 kg vs -1.0 kg, p<0.0001). Greater proportions of patients treated withliraglutide experienced transient nausea vs patients treated with sitagliptin (20.8% and 27.1% forliraglutide vs 4.6% for sitagliptin). The reductions in HbA1c and superiority vs sitagliptin observedafter 26 weeks of liraglutide treatment (1.2 mg and 1.8 mg) were sustained after 52 weeks of treatment(-1.29% and -1.51% vs -0.88%, p<0.0001). Switching patients from sitagliptin to liraglutide after52 weeks of treatment resulted in additional and statistically significant reduction in HbA1c (-0.24%and -0.45%, 95% CI: -0.41 to -0.07 and -0.67 to -0.23) at week 78, but a formal control group was notavailable.

In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg once daily and exenatide10 mcg twice daily in patients inadequately controlled on metformin and/or sulfonylurea therapy(mean HbA1c 8.3%), liraglutide was statistically superior to exenatide treatment in reducing HbA1cafter 26 weeks (-1.12% vs -0.79%; estimated treatment difference: -0.33; 95% CI: -0.47 to -0.18).

Significantly more patients achieved HbA1c below 7% with liraglutide compared with exenatide(54.2% vs 43.4%, p=0.0015). Both treatments resulted in mean body weight loss of approximately3 kg. Switching patients from exenatide to liraglutide after 26 weeks of treatment resulted in anadditional and statistically significant reduction in HbA1c (-0.32%, 95% CI: -0.41 to -0.24) at week 40,but a formal control group was not available. During the 26 weeks, there were 12 serious events in 235patients (5.1%) using liraglutide, whereas there were 6 serious adverse events in 232 patients (2.6%)using exenatide. There was no consistent pattern with respect to system organ class of events.

In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg with lixisenatide 20 mcgin 404 patients inadequately controlled on metformin therapy (mean HbA1c 8.4%), liraglutide wassuperior to lixisenatide in reducing HbA1c after 26 weeks of treatment (-1.83% vs -1.21%, p<0.0001).

Significantly more patients achieved HbA1c below 7% with liraglutide compared to lixisenatide(74.2% vs 45.5%, p<0.0001), as well as the HbA1c target below or equal 6.5% (54.6% vs 26.2%,p<0.0001). Body weight loss was observed in both treatment arms (-4.3 kg with liraglutide and -3.7 kgwith lixisenatide). Gastrointestinal adverse events were more frequently reported with liraglutidetreatment (43.6% vs 37.1%).

The absorption of liraglutide following subcutaneous administration is slow, reaching maximumconcentration 8-12 hours post dosing. Estimated maximum liraglutide concentration was 9.4 nmol/l(mean body weight approximately 73 kg) for a subcutaneous single dose of liraglutide 0.6 mg. At1.8 mg liraglutide, the average steady state concentration of liraglutide (AUCτ/24) reachedapproximately 34 nmol/l (mean body weight approximately 76 kg). The exposure of liraglutidedecreases with increasing body weight. Liraglutide exposure increased proportionally with dose. Theintra-subject coefficient of variation for liraglutide AUC was 11% following single doseadministration.

Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

The apparent volume of distribution after subcutaneous administration is 11-17 l. The mean volume ofdistribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively boundto plasma proteins (>98%).

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

Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minorpart of the administered radioactivity was excreted as liraglutide-related metabolites in urine or faeces(6% and 5%, respectively). The urine and faeces radioactivity was mainly excreted during the first 6-8 days, and corresponded to three minor metabolites, respectively.

The mean clearance following subcutaneous administration of a single dose liraglutide isapproximately 1.2 l/h with an elimination half-life of approximately 13 hours.

Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from apharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of patients(18 to 80 years).

Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the resultsof population pharmacokinetic data analysis of male and female patients and a pharmacokinetic studyin healthy subjects.

Ethnic origin had no clinically relevant effect on the pharmacokinetics of liraglutide based on theresults of population pharmacokinetic analysis which included patients of White, Black, Asian and

Hispanic groups.

Obesity

Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect onthe pharmacokinetics of liraglutide.

The pharmacokinetics of liraglutide was evaluated in patients with varying degree of hepaticimpairment in a single-dose trial. Liraglutide exposure was decreased by 13-23% in patients with mildto moderate hepatic impairment compared to healthy subjects.

Exposure was significantly lower (44%) in patients with severe hepatic impairment (Child Pughscore >9).

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

Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment(CrCL 30-59 ml/min, see section 5.1) had 26% lower liraglutide exposure when compared with aseparate trial including patients with type 2 diabetes with normal renal function or mild renalimpairment.

Pharmacokinetic properties were assessed in clinical studies in the paediatric population with type 2diabetes aged 10 years and above. The liraglutide exposure in adolescents and children wascomparable to that observed in the adult population.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, 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 inmonkeys 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 forhumans is likely to be low but cannot be completely excluded. No other treatment-related tumourshave been found.

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

Disodium phosphate dihydrate

Phenol

Water for injections

Substances added to Victoza may cause degradation of liraglutide. In the absence of compatibilitystudies, this medicinal product must not be mixed with other medicinal products.

30 months.

After first use: 1 month.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store away from the freezer compartment.

After first use: Store below 30°C or store in a refrigerator (2°C-8°C). Do not freeze.

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

Cartridge (type 1 glass) with a plunger (bromobutyl) and a laminate rubber sheet(bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polyolefin andpolyacetal.

Each pen contains 3 ml solution, delivering 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of1.8 mg.

Pack sizes of 1, 2, 3, 5 or 10 pre-filled pens.

Not all pack sizes may be marketed.

Victoza should not be used if it does not appear clear and colourless or almost colourless.

Victoza should not be used if it has been frozen.

Victoza can be administered with needles up to a length of 8 mm and as thin as 32G. The pen isdesigned to be used with NovoFine or NovoTwist disposable needles.

Needles are not included.

The patient should be advised to discard the injection needle in accordance with local requirementsafter each injection and store the pen without an injection needle attached. This preventscontamination, infection and leakage. It also ensures that the dosing is accurate.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/09/529/001-005

Date of first authorisation: 30 June 2009

Date of last renewal: 11 April 2014

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

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