פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר באפריל 2015

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1 פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר באפריל NAME OF THE MEDICINAL PRODUCT Victoza 6 mg/ml solution for injection in pre filled pen 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One 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 PHARMACEUTICAL FORM Solution for injection. Clear, colourless or almost colourless, isotonic solution; ph= CLINICAL PARTICULARS 4.1 Therapeutic indications Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control in combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations). 4.2 Posology and method of administration Posology To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least one week, the dose should be increased to 1.2 mg. Some patients are expected to benefit from an increase in dose from 1.2 mg to 1.8 mg and based on clinical response, after at least one week, the dose can be increased to 1.8 mg to further improve glycaemic control. Daily doses higher than 1.8 mg are not recommended. Victoza can be added to existing metformin or to a combination of metformin and thiazolidinedione therapy. The current dose of metformin and thiazolidinedione can be continued unchanged. Victoza can be added to existing sulfonylurea or to a combination of metformin and sulfonylurea therapy or a basal insulin. When Victoza is added to sulfonylurea therapy or basal insulin, a reduction in the dose of sulfonylurea or basal insulin should be considered to reduce the risk of hypoglycaemia (see section 4.4). Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza. However, when initiating treatment with Victoza in combination with a sulfonylurea or a basal insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulfonylurea or the basal insulin. 1

2 Special populations Elderly patients (>65 years old) No dose adjustment is required based on age. Therapeutic experience in patients 75 years of age is limited (see section 5.2). Patients with renal impairment No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance ml/min and ml/min, respectively). There is no therapeutic experience in patients with severe renal impairment (creatinine clearance below 30 ml/min). Victoza can currently not be recommended for use in patients with severe renal impairment including patients with end stage renal disease (see section 5.2). Patients with hepatic impairment The therapeutic experience in patients with all degrees of hepatic impairment is currently too limited to recommend the use in patients with mild, moderate or severe hepatic impairment (see section 5.2). Paediatric population The safety and efficacy of Victoza in children and adolescents below age 18 have not been established (see section 5.1). No data are available. Method of administration Victoza must not be administered intravenously or intramuscularly. Victoza is administered once daily at any time, independent of meals, and can be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site and timing can be changed without dose adjustment. However, it is preferable that Victoza is injected around the same time of the day, when the most convenient time of the day has been chosen. For further instructions on administration, see section Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section Special warnings and precautions for use Liraglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Liraglutide is not a substitute for insulin. There is limited experience in patients with congestive heart failure New York Heart Association (NYHA) class I II and liraglutide should therefore be used with caution. There is no experience in patients with congestive heart failure NYHA class III-IV and liraglutide is therefore not recommended 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 transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea. Acute pancreatitis Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Victoza should be discontinued; if acute pancreatitis is confirmed, Victoza should not be restarted. Caution should be exercised in patients with 2

3 a history of pancreatitis. Thyroid disease Thyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials in particular in patients with pre existing thyroid disease and liraglutide should therefore be used with caution. Hypoglycaemia Patients receiving liraglutide in combination with a sulfonylurea or a basal insulin may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by a reduction in the dose of sulfonylurea or basal insulin. Dehydration Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in patients treated with liraglutide. Patients treated with liraglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion. 4.5 Interaction with other medicinal products and other forms of interaction In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 and plasma protein binding. 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 and therefore no dose adjustment is required. Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicinal products. 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 liraglutide 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 1000 mg. Paracetamol C max was decreased by 31% and median t max 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 clinically relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin C max was decreased by 38% and median t max 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 C max increased by 37% while median t max did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are 3

4 not required. Digoxin A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC by 16%; C max decreased by 31%. Digoxin median t max was delayed from 1 h to 1.5 h. No adjustment of digoxin dose 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%; C max decreased by 27%. Lisinopril median t max 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 ethinyloestradiol and levonorgestrel C max by 12 and 13%, respectively, following administration of a single dose of an oral contraceptive product. T max was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinyloestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide. Insulin No pharmacokinetic or pharmacodynamic interactions were observed between liraglutide and insulin detemir when administering a single dose of insulin detemir 0.5 U/kg with liraglutide 1.8 mg at steady state in patients with type 2 diabetes. 4.6 Fertility, pregnancy and lactation Pregnancy There are no adequate data from the use of liraglutide in pregnant women. Studies in animals have shown 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 a patient wishes to become pregnant, or pregnancy occurs, treatment with Victoza should be discontinued. Breast-feeding It is not known whether liraglutide is excreted in human milk. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk is low. Non-clinical studies have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3). Because of lack of experience, Victoza should not be used during breast-feeding. Fertility Apart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility. 4.7 Effects on ability to drive and use machines 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 using machines, in particular when Victoza is used in combination with a sulfonylurea or a basal insulin. 4

5 4.8 Undesirable effects Summary of the safety profile In five large long-term clinical trials over 2,500 patients have received treatment with Victoza alone or in combination with metformin, a sulfonylurea (with or without metformin) or metformin 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, and dyspepsia were common. At the beginning of the therapy, these gastrointestinal adverse reactions may occur more frequently. These reactions usually diminish within a few days or weeks on continued treatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia was common, and very common when liraglutide is used in combination with a sulfonylurea. Major hypoglycaemia has primarily been observed when combined with a sulfonylurea. Tabulated list of adverse reactions Table 1 lists adverse reactions reported in long term phase 3 controlled trials and spontaneous (postmarketing) reports. Frequencies for related spontaneous reports (postmarketing) have been calculated based on their incidence in phase 3 clinical trials. Frequencies 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Adverse reactions from long-term controlled phase 3 trials and spontaneous (postmarketing) reports MedDRA system organ classes Infections and infestations Immune system disorders Metabolism and nutrition disorders Nervous system disorders Cardiac disorders Gastrointestinal disorders Skin and subcutaneous Very common Nausea Diarrhoea Common Uncommon Rare Very rare Nasopharyngitis Bronchitis Hypoglycaemia Anorexia Appetite decreased Headache Dizziness Increased heart rate Vomiting Dyspepsia Abdominal pain upper Constipation Gastritis Flatulence Abdominal distension Gastroesophageal reflux disease Abdominal discomfort Toothache Rash Dehydration Urticaria Pruritus Anaphylactic reactions Intestinal obstruction Pancreatitis (including necrotising pancreatitis) 5

6 tissue disorder Renal and urinary disorders General disorders and administration site conditions Fatigue Injection site reactions Renal impairment Renal failure acute Malaise Description of selected adverse reactions In a clinical trial with liraglutide as monotherapy, rates of hypoglycaemia reported with liraglutide were lower than rates reported for patients treated with active comparator (glimepiride). The most frequently reported adverse reactions were gastrointestinal disorders, infections and infestations. Hypoglycaemia Most episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of major hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Major hypoglycaemia may occur uncommonly and has primarily been observed when liraglutide is combined with a sulfonylurea (0.02 events/patient year). Very few episodes (0.001 events/patient year) were observed with administration of liraglutide in combination with oral antidiabetics other than sulfonylureas. The risk of hypoglycaemia is low with combined use of basal insulin and liraglutide (1.0 events per patient year, see section 5.1). Gastrointestinal adverse reactions When combining liraglutide with metformin, 20.7% of patients reported at least one episode of nausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining liraglutide with a sulfonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patients reported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in a dose dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea. Patients >70 years may experience more gastrointestinal effects when treated with liraglutide. Patients with mild renal impairment (creatinine clearance ml/min and ml/min, respectively) may experience more gastrointestinal effects when treated with liraglutide. Withdrawal The incidence of withdrawal due to adverse reactions was 7.8% for liraglutide-treated patients and 3.4% for comparator treated patients in the long-term controlled trials (26 weeks or longer). The most frequent adverse reactions leading to withdrawal for liraglutide-treated patients were nausea (2.8% of patients) and vomiting (1.5%). Injection site reactions Injection site reactions have been reported in approximately 2% of patients receiving Victoza in longterm (26 weeks or longer) controlled trials. These reactions have usually been mild. Pancreatitis Few cases (<0.2%) of acute pancreatitis have been reported during long-term clinical trials with Victoza. Pancreatitis was also reported post-marketing. Allergic reactions 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%) of 6

7 angioedema have been reported during all long-term clinical trials with Victoza. 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 to the Ministry of Health according to the National Regulation by using an online form ealth.gov.il ) or by (adr@moh.health.gov.il). 4.9 Overdose From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the recommended maintenance dose. Events reported included severe nausea and severe vomiting. None of the reports included severe hypoglycaemia. All patients recovered without complications. In the event of overdose, appropriate supportive treatment should be initiated according to the patient s clinical signs and symptoms. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. insulins. ATC code: A10BX07 Mechanism of action Liraglutide is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Unlike native GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. 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 4 (DPP-4) and neutral endopeptidase (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 in cyclic adenosine monophosphate (camp). Liraglutide stimulates insulin secretion in a glucosedependent manner. Simultaneously, liraglutide lowers inappropriately high glucagon secretion, also 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. Pharmacodynamic effects Liraglutide has 24-hour duration of action and improves glycaemic control by lowering fasting and postprandial blood glucose in patients with type 2 diabetes mellitus. Clinical efficacy and safety Five double-blind, randomised, controlled clinical trials were conducted to evaluate the effects of liraglutide on glycaemic control (Table 2-5). Treatment with liraglutide produced clinically and 7

8 statistically significant improvements in glycosylated haemoglobin A 1c (HbA 1c ), fasting plasma glucose and postprandial glucose compared with placebo. These trials included 3,978 exposed patients with type 2 diabetes (2,501 patients treated with Victoza), 53.7% men and 46.3% women, 797 patients (508 treated with liraglutide) were 65 years of 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 subjects per trial) and one double-blind, randomised, controlled clinical trial in subjects with type 2 diabetes and moderate renal impairment (279 patients). Glycaemic control Combination with oral antidiabetics Liraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA 1c compared with patients receiving placebo (Tables 2 to 5). Placebo Glimepiride 1 Combination with metformin Table 2 Victoza in combination with metformin (26 weeks) Metformin 1.8 mg liraglutide 1.2 mg liraglutide add-on therapy + metformin 2 + metformin 2 + metformin 2 + metformin 2 N Mean HbA 1c (%) Change from baseline Patients (%) achieving HbA 1c <7% All patients Previous OAD monotherapy Mean body weight (kg) Change from baseline glimepiride 4 mg/day; 2 metformin 2,000 mg/day Combination with sulfonylurea Table 3 Victoza in combination with glimepiride (26 weeks) Glimepiride add-on therapy 1.8 mg liraglutide + glimepiride mg liraglutide + glimepiride 2 Placebo + glimepiride 2 Rosiglitazone 1 + glimepiride 2 N Mean HbA 1c (%) Change from baseline Patients (%) achieving HbA 1c <7% All patients Previous OAD monotherapy Mean body weight (kg) Change from baseline Rosiglitazone 4 mg/day; 2 glimepiride 4 mg/day

9 Combination with thiazolidinedione and metformin Table 4 Victoza in combination with metformin + rosiglitazone (26 weeks) Metformin + rosiglitazone add-on therapy 1.8 mg liraglutide + metformin 1 + rosiglitazone mg liraglutide + metformin 1 + rosiglitazone 2 Placebo + metformin 1 + rosiglitazone 2 N Mean HbA 1c (%) Change from baseline Patients (%) achieving HbA 1c <7% All patients Mean body weight (kg) Change from baseline Metformin 2,000 mg/day; 2 rosiglitazone 4 mg twice daily N/A Combination with sulfonylurea and metformin Table 5 Victoza in combination with glimepiride + metformin (26 weeks) Metformin + glimepiride add-on therapy 1.8 mg liraglutide + metformin 2 + glimepiride 3 N/A Placebo + metformin 2 + glimepiride 3 N Mean HbA 1c (%) Change from baseline Insulin glargine 1 + metformin 2 + glimepiride Patients (%) achieving HbA 1c <7% All patients Mean body weight (kg) Change from baseline The dosing of insulin glargine was open-labelled and was applied according to the following titration guideline. Titration of the insulin glargine dose was managed by the patient after instruction by the investigator. 2 Metformin 2,000 mg/day; 3 glimepiride 4 mg/day. 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 IU a 6.7 mmol/l ( 120 mg/dl) 2 IU a According to the individualised recommendation by the investigator at the previous visit, for example depending 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 in combination with metformin achieved a target HbA 1c <7% and the remaining patients continued in a 26-week open label trial and were randomised to add liraglutide or a single dose of insulin aspart (with the largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% in order to minimize the risk of hypoglycaemia. Addition of liraglutide resulted in a statistically significantly greater reduction of HbA 1c (-0.73% for liraglutide vs -0.40% for comparator) and body weight (-3.03 vs 0.72 kg). The rate of hypoglycaemic episodes (per patient year of exposure) was statistically significantly lower when adding liraglutide compared to adding a single dose of insulin aspart (1.0 vs 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21). 9

10 In a 52-week clinical trial, the addition of insulin detemir to liraglutide 1.8 mg and metformin in patients not achieving glycaemic targets on liraglutide and metformin alone resulted in a HbA 1c decrease from baseline of 0.54%, compared to 0.20% in the liraglutide 1.8 mg and metformin control group. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemic episodes (0.23 versus 0.03 events per patient years). Use in patients with renal impairment In a double-blind trial comparing the efficacy and safety of liraglutide 1.8 mg versus placebo as addon to insulin and/or OAD in patients with type 2 diabetes and moderate renal impairment, liraglutide was superior to placebo treatment in reducing HbA 1c after 26 weeks ( 1.05% vs 0.38%). Significantly more patients achieved HbA 1c below 7% with liraglutide compared with placebo (52.8% vs 19.5%). In both groups a decrease in body weight was seen: 2.4 kg with liraglutide vs 1.09 with placebo. There was a comparable risk of hypoglycaemic episodes between the two treatment groups. The safety profile of liraglutide was generally similar to that observed in other studies with liraglutide. Proportion of patients achieving reductions in HbA 1c Liraglutide in combination with metformin, glimepiride, or metformin and rosiglitazone resulted in a statistically significant (p ) greater proportion of patients achieving an HbA 1c 6.5% at 26 weeks compared with patients receiving these agents alone. Fasting plasma glucose Treatment with liraglutide alone or in combination with one or two oral antidiabetic drugs resulted in a reduction in fasting plasma glucose of mg/dl ( mmol/l). This reduction was observed within the first two weeks of treatment. Postprandial glucose Liraglutide reduces postprandial glucose across all three daily meals by mg/dl ( mmol/l). Beta-cell function Clinical trials with liraglutide indicate improved beta-cell function based on measures such as the homeostasis 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 was demonstrated in a subset of patients with type 2 diabetes (N=29). Body weight Liraglutide in combination with metformin, metformin and glimepiride or metformin and rosiglitazone was associated with sustained weight reduction over the duration of trials in a range from 1.0 kg to 2.8 kg. Larger weight reduction was observed with increasing body mass index (BMI) at baseline. Cardiovascular evaluation Blood pressure Over the duration of the trials, liraglutide decreased the systolic blood pressure on average of 2.3 to 6.7 mmhg from baseline and compared to active comparator the decrease was 1.9 to 4.5 mmhg. Post-hoc analysis of serious major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) from all intermediate and long-term phase 2 and 3 trials (ranging from 26 and up to 100 weeks duration) including 5,607 patients (3,651 exposed to liraglutide), showed no increase in cardiovascular risk (incidence ratio of 0.75 (95% CI 0.35; 1.63) for the composite endpoint for liraglutide versus all comparators (metformin, glimepiride, rosiglitazone, insulin glargine, placebo)). High-risk cardiovascular patients were excluded from the trials and the incidence rates of serious major cardiovascular events in the trials were low (6.02 per 1,000 patient years in liraglutide-treated patients and in all-comparator-treated patients), precluding firm conclusions. 10

11 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-liraglutide antibodies following treatment with liraglutide. On average, 8.6% of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of liraglutide. Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with Victoza in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use). Other clinical data In an open label trial comparing the efficacy and safety of liraglutide (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA 1c 8.5%), liraglutide at both doses was statistically superior to sitagliptin treatment in reducing HbA 1c after 26 weeks ( 1.24%, 1.50% vs 0.90%, p<0.0001). Patients treated with liraglutide had a significant decrease in body weight compared to that of patients treated with sitagliptin ( 2.9 kg and 3.4 kg vs 1.0 kg, p ). Greater proportions of patients treated with liraglutide experienced transient nausea vs patients treated with sitagliptin (20.8% and 27.1% for liraglutide vs. 4.6% for sitagliptin). The reductions in HbA 1c and superiority vs sitagliptin observed after 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 ). Switching patients from sitagliptin to liraglutide after 52 weeks of treatment resulted in additional and statistically significant reduction in HbA 1c ( 0.24% and 0.45%, 95% CI: 0.41 to 0.07 and to 0.23 ) at week 78, but a formal control group was not available. In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg once daily and exenatide 10 mcg twice daily in patients inadequately controlled on metformin and/or sulfonylurea therapy (mean HbA 1c 8.3%), liraglutide was statistically superior to exenatide treatment in reducing HbA 1c after 26 weeks ( 1.12% vs 0.79%; estimated treatment difference: 0.33; 95% CI: 0.47 to 0.18). Significantly more patients achieved HbA 1c below 7% with liraglutide compared with exenatide (54.2% vs 43.4%, p=0.0015). Both treatments resulted in mean body weight loss of approximately 3 kg. Switching patients from exenatide to liraglutide after 26 weeks of treatment resulted in an additional and statistically significant reduction in HbA 1c ( 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 235 patients (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. 5.2 Pharmacokinetic properties Absorption The absorption of liraglutide following subcutaneous administration is slow, reaching maximum concentration 8 12 hours post dosing. Estimated maximum liraglutide concentration was 9.4 nmol/l for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUC τ/24 ) reached approximately 34 nmol/l. Liraglutide exposure increased proportionally with dose. The intra-subject coefficient of variation for liraglutide AUC was 11% following single dose administration. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%. Distribution The apparent volume of distribution after subcutaneous administration is l. The mean volume of distribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively bound 11

12 to plasma proteins (>98%). Biotransformation During 24 hours following administration of a single radiolabelled [ 3 H]-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 Following a [ 3 H]-liraglutide dose, intact liraglutide was not detected in urine or faeces. Only a minor part 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 is approximately 1.2 l/h with an elimination half-life of approximately 13 hours. Special populations Elderly patients: Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a pharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of patients (18 to 80 years). Gender: Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of male and female patients and a pharmacokinetic study in healthy subjects. Ethnic origin: Ethnic origin had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results 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 on the pharmacokinetics of liraglutide. Hepatic impairment: The pharmacokinetics of liraglutide was evaluated in patients with varying degree 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). Renal impairment: 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 28%, respectively, in patients with mild (creatinine clearance, CrCl ml/min), moderate (CrCl ml/min), and severe (CrCl <30 ml/min) renal impairment and in end-stage renal disease requiring dialysis. Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment (CrCL ml/min, see section 5.1) 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. 12

13 5.3 Preclinical safety data Non-clinical data reveal no special hazards for humans 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 Victoza 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 Victoza, 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. Following intra-arterial injection of liraglutide to rabbits, slight to moderate haemorrhage, erythema and swelling at the injection site were observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Disodium phosphate dihydrate Propylene glycol Phenol Water for injections 6.2 Incompatibilities Substances added to Victoza may cause degradation of liraglutide. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 30 months. After first use: 1 month. 6.4 Special precautions for storage 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. 6.5 Nature and contents of container Cartridge (type 1 glass) with a plunger (bromobutyl) and a stopper (bromobutyl/polyisoprene) 13

14 contained in a pre-filled multidose disposable pen made of polyolefin and polyacetal. Each pen contains 3 ml solution, delivering 30 doses of 0.6 mg, 15 doses of 1.2 mg or 10 doses of 1.8 mg. Pack sizes of 1, 2, 3, 5 or 10 pre-filled pens. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling 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 is designed 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 requirements after each injection and store the pen without an injection needle attached. This prevents contamination, infection and leakage. It also ensures that the dosing is accurate. 7. Registration number: Victoza : Manufacturer: Novo Nordisk A/S Novo Allé DK-2880 Bagsværd Denmark 9. Marketing Authorisation Holder: Novo Nordisk Ltd. 20 HaTa as St. Indust. Area, Kfar Saba, The content of this leaflet was checked and approved by the Ministry of Health on April