liraglutide: prescribing information – dosing, contraindications, interactions, side effects

Adults

Ablymico is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of:
- ≥ 30 kg/m2 (obesity), or
- ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea.

Treatment with Ablymico should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5 % of their initial body weight.

Adolescents (≥ 12 years)

Ablymico can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with:

• obesity (BMI corresponding to ≥ 30 kg/m2 for adults by international cut-off points)* and • body weight above 60 kg.

Treatment with Ablymico should be discontinued and re-evaluated if patients have not lost at least 4 % of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose.

*IOTF BMI cut-off points for obesity by sex between 12-18 years (see table 1), in accordance with study design of the Trial 4180, see section 5.1.

Table 1 IOTF BMI cut-off points for obesity by sex between 12-18 years
Age (years)
BMI corresponding to 30 kg/m2 for adults by international cut-off points.
Males
Females

Posology

Adults

The starting dose is 0.6 mg once daily. The dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastrointestinal tolerability (see table 3). If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Daily doses higher than 3.0 mg are not recommended.

Table 3 Dose escalation schedule

Dose
Weeks
Dose escalation
4 weeks
0.6 mg
1.2 mg
1.8 mg
2.4 mg
Maintenance dose
3.0 mg

Adolescents (≥ 12 years)

For adolescents from the age of 12 to below 18 years old a similar dose escalation schedule as for adults should be applied (see table 3). The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3.0 mg are not recommended.

Children (6 to < 12 years)

For children from the age of 6 to below 12 years old a similar dose escalation schedule as for adults should be applied (see table 3). The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3.0 mg are not recommended.
Liraglutide in children should be initiated by a physician experienced in the management of obesity in children.

Missed doses

If a dose is missed within 12 hours from when it is usually taken, the patient should take the dose as soon as possible. If there is less than 12 hours to the next dose, the patient should not take the missed dose and resume the once-daily regimen with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose.

Patients with type 2 diabetes mellitus

Ablymico should not be used in combination with another GLP-1 receptor agonist.

When initiating Ablymico, it should be considered to reduce the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues (see section 4.4).

Special populations

Elderly (≥ 65 years old)
No dose adjustment is required based on age. Therapeutic experience in patients ≥ 75 years of age is limited and use in these patients is not recommended (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min). Ablymico is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Ablymico is not recommended for use in patients with severe hepatic impairment and should be used cautiously in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

Paediatric population

No dose adjustment is required for adolescents and children from the age of 6 years and above.
The safety and efficacy of liraglutide in children below 6 years of age has not been established (see section 5.1).

Method of administration

Ablymico is for subcutaneous use only. It must not be administered intravenously or intramuscularly.

Ablymico is administered once daily at any time, independent of meals. It should be injected in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment.
However, it is preferable that Ablymico is injected around the same time of the day, when the most convenient time of the day has been chosen. Injection sites should always be rotated 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.

Summary of the safety profile:

Liraglutide was evaluated for safety in 5 double-blind, placebo-controlled trials that enrolled 5 813 adult patients with overweight or obesity with at least one weight-related comorbidity. Overall, gastrointestinal reactions were the most frequently reported adverse reactions during treatment (67.9 %) (see section ‘Description of selected adverse reactions’).

Tabulated list of adverse reactions

Table 4 lists adverse reactions reported in adults. Adverse reactions are 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions reported in adults
MedDRA system organ classes
Very common
Common
Uncommon
Rare
Not known
Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypoglycaemia*
Dehydration

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Not known
Psychiatric disorders

Insomnia**

Nervous system disorders
Headache
Dizziness
Dysgeusia

Cardiac disorders

Tachycardia

Gastrointestinal disorders
Nausea
Vomiting
Diarrhoea
Constipation
Dry mouth
Dyspepsia
Gastritis
Gastro- oesophageal reflux disease
Abdominal pain upper
Flatulence
Eructation
Abdominal distension
Pancreatitis***
Delayed gastric emptying****

Intestinal obstruction†
Hepatobiliary disorders

Cholelithiasis***
Cholecystitis**
*

Skin and subcutaneous tissue disorders

Rash
Urticaria

Cutaneous amyloidosis
Renal and urinary disorders

Acute renal failure
Renal impairment

General disorders and administration site conditions

Injection site reactions
Asthenia
Fatigue
Malaise

Investigations

Increased lipase
Increased amylase

*
Hypoglycaemia (based on self-reported symptoms by patients and not confirmed by blood glucose measurements) reported in patients without type 2 diabetes mellitus treated with liraglutide in combination with diet and exercise. Please see section ‘Description of selected adverse reactions’ for further information.
**
Insomnia was mainly seen during the first 3 months of treatment.
*** See section 4.4.
**** From controlled phase 2, 3a and 3b clinical trials.
†
ADR from post marketing sources.

Description of selected adverse reactions:

Hypoglycaemia in patients without type 2 diabetes mellitus
In clinical trials in overweight or obese patients without type 2 diabetes mellitus treated with liraglutide in combination with diet and exercise, no severe hypoglycaemic events (requiring third party assistance) were reported. Symptoms of hypoglycaemic events were reported by 1.6 % of patients treated with liraglutide and 1.1 % of patients treated with placebo; however, these events were not confirmed by blood glucose measurements. The majority of events were mild.

Hypoglycaemia in patients with type 2 diabetes mellitus
In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with liraglutide in combination with diet and exercise, severe hypoglycaemia (requiring third party assistance) was reported by 0.7 % of patients treated with liraglutide and only in patients concomitantly treated with

sulfonylurea. Also, in these patients documented symptomatic hypoglycaemia was reported by 43.6 % of patients treated with liraglutide and in 27.3 % of patients treated with placebo. Among patients not concomitantly treated with sulfonylurea, 15.7 % of patients treated with liraglutide and 7.6 % of patients treated with placebo reported documented symptomatic hypoglycaemic events (defined as plasma glucose ≤ 3.9 mmol/l accompanied by symptoms).

Hypoglycaemia in patients with type 2 diabetes mellitus treated with insulin
In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with insulin and liraglutide 3.0 mg/day in combination with diet and exercise and up to 2 OADs, severe hypoglycaemia (requiring third party assistance) was reported by 1.5 % of patients treated with liraglutide 3.0 mg/day.
In this trial, documented symptomatic hypoglycaemia (defined as plasma glucose ≤ 3.9 mmol/l accompanied by symptoms) was reported by 47.2 % of patients treated with liraglutide 3.0 mg/day and by 51.8 % of patients treated with placebo. Among patients concomitantly treated with sulfonylurea, 60.9 % of patients treated with liraglutide 3.0 mg/day and 60.0 % of patients treated with placebo reported documented symptomatic hypoglycaemic events.

Gastrointestinal adverse reactions
Most episodes of gastrointestinal events were mild to moderate, transient and the majority did not lead to discontinuation of therapy. The reactions usually occurred during the first weeks of treatment and diminished within a few days or weeks on continued treatment.

Patients ≥ 65 years of age may experience more gastrointestinal effects when treated with liraglutide.

Patients with mild or moderate renal impairment (creatinine clearance ≥ 30 mL/min) may experience more gastrointestinal effects when treated with liraglutide.

Acute renal failure
In patients treated with GLP-1 receptor agonists, there have been reports of acute renal failure. A majority of the reported events occurred in patients who had experienced nausea, vomiting or diarrhoea leading to volume depletion (see section 4.4).

Allergic reactions
Few cases of anaphylactic reactions with symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life threatening. If an anaphylactic reaction is suspected, liraglutide should be discontinued and treatment should not be restarted (see section 4.3).

Injection site reactions
Injection site reactions have been reported in patients treated with liraglutide. These reactions were usually mild and transitory and the majority disappeared during continued treatment.

Tachycardia
In clinical trials, tachycardia was reported in 0.6 % of patients treated with liraglutide and in 0.1 % of patients treated with placebo. The majority of events were mild or moderate. Events were isolated and the majority resolved during continued treatment with liraglutide.

Cutaneous amyloidosis
Cutaneous amyloidosis may occur at the injection site (see section 4.2).

Paediatric population

In a clinical trial conducted in adolescents of 12 years to less than 18 years with obesity, 125 patients were exposed to liraglutide for 56 weeks.
Overall, the frequency, type and severity of adverse reactions in the adolescents with obesity were comparable to that observed in the adult population. Vomiting occurred with a 2-fold higher frequency in adolescents compared to adults.

The percentage of patients reporting at least one episode of clinically significant hypoglycaemia was higher with liraglutide (1.6 %) compared to placebo (0.8 %). No severe hypoglycaemic episodes occurred in the trial.

In a clinical trial conducted in children of 6 to less than 12 years with obesity (Trial 4392), 56 patients were exposed to liraglutide for 56 weeks.

Overall, the frequency, type and severity of adverse reactions in the children with obesity were comparable to that observed in the adolescent and adult population.

Children reported more GI events in both liraglutide and placebo groups compared to adolescents and adults, with a 2-fold increase in vomiting observed in children compared to adolescents.

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.

Aspiration in association with general anaesthesia or deep sedation

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

Patients with heart failure

There is no clinical 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.

Special populations

The safety and efficacy of liraglutide for weight management have not been established in patients:
- aged 75 years or more,
- treated with other products for weight management,
- with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain,
- with severe renal impairment,
- with severe hepatic impairment.
Use in these patients is not recommended (see section 4.2).
As liraglutide for weight management was not investigated in subjects with mild or moderate hepatic impairment, it should be used with caution in these patients (see sections 4.2 and 5.2).

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.

Pancreatitis

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, liraglutide should be discontinued; if acute pancreatitis is confirmed, liraglutide should not be restarted.

Cholelithiasis and cholecystitis

In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients treated with liraglutide than in patients on placebo. The fact that substantial weight loss can increase the risk of cholelithiasis and thereby cholecystitis only partially explained the higher rate with liraglutide. Cholelithiasis and cholecystitis may lead to hospitalisation and cholecystectomy. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid disease

In clinical trials in type 2 diabetes, thyroid adverse events, such as goitre, have been reported in particular in patients with pre-existing thyroid disease. Liraglutide should therefore be used with caution in patients with thyroid disease.

Heart rate

An increase in heart rate was observed with liraglutide in clinical trials (see section 5.1). Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should be informed of the symptoms of increased heart rate (palpitations or feelings of a racing heartbeat while at rest). For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with liraglutide should be discontinued.

Dehydration

Signs and symptoms of dehydration, including renal impairment and acute renal failure, have been reported in patients treated with GLP-1 receptor agonists. 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.

Hypoglycaemia in patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus receiving liraglutide in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of insulin and/or sulfonylurea.

Paediatric population

Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥ 12 years) treated with liraglutide. Patients should be informed about the characteristic symptoms of hypoglycaemia and the appropriate actions.

Hyperglycaemia in insulin treated patients with diabetes mellitus

In patients with diabetes mellitus liraglutide must not be used as a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin (see section 4.2).

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 (CYP) 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.

Interaction studies have been performed with 1.8 mg liraglutide. The effect on rate of gastric emptying was equivalent between liraglutide 1.8 mg and 3.0 mg, (paracetamol AUC0-300 min). 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 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 International Normalised Ratio (INR) is recommended.

Paracetamol (Acetaminophen)

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 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 tmax was delayed 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.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are limited 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. If a patient wishes to become pregnant or pregnancy occurs, treatment with liraglutide 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, liraglutide 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 (see section 5.3).

Liraglutide has no or negligible influence on the ability to drive and use machines. However, dizziness can be experienced mainly during the first 3 months of treatment with liraglutide. Driving or use of machines should be exercised with caution if dizziness occurs.

From clinical trials and post-marketing use of liraglutide overdoses have been reported up to 72 mg (24 times the recommended dose for weight management). Events reported included severe nausea, severe vomiting and severe hypoglycaemia.

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) analogue with 97 % amino acid sequence homology to endogenous human GLP-1. Liraglutide binds to and activates the GLP-1 receptor (GLP-1R).

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

Liraglutide lowers body weight in humans mainly through loss of fat mass with relative reductions in visceral fat being greater than for subcutaneous fat loss. Liraglutide regulates appetite by increasing feelings of fullness and satiety, while lowering feelings of hunger and prospective food consumption, thereby leading to reduced food intake. Liraglutide does not increase energy expenditure compared to placebo.

Liraglutide stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner which results in a lowering of fasting and post-prandial glucose. The glucose-lowering effect is more pronounced in patients with prediabetes and diabetes compared to patients with normoglycaemia.
Clinical trials suggest that liraglutide improves and sustains beta-cell function, according to HOMA-B and the proinsulin-to-insulin ratio.

Clinical efficacy and safety

The efficacy and safety of liraglutide for weight management in conjunction with reduced calorie intake and increased physical activity were studied in four phase 3 randomised, double-blind, placebo- controlled trials which included a total of 5 358 adult patients.

- Trial 1 (SCALE Obesity & Pre-Diabetes – 1839): A total of 3 731 patients with obesity (BMI ≥ 30 kg/m²) or with overweight (BMI ≥ 27 kg/m²) with dyslipidaemia and/or hypertension were stratified according to prediabetes status at screening and BMI at baseline (≥ 30 kg/m² or < 30 kg/m²). All 3 731 patients were randomised to 56 weeks of treatment and the 2 254 patients with prediabetes at screening were randomised to 160 weeks of treatment. Both treatment periods were followed by a 12-week off drug/placebo observational follow-up period.
Lifestyle intervention in the form of an energy-restricted diet and exercise counselling was background therapy for all patients.

Absorption

The absorption of liraglutide following subcutaneous administration was slow, reaching maximum concentration approximately 11 hours post dosing. The average liraglutide steady state concentration (AUCτ/24) reached approximately 31 nmol/l in obese (BMI 30-40 kg/m2) patients following administration of 3 mg liraglutide. Liraglutide exposure increased proportionally with dose. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55 %.

Distribution

The mean apparent volume of distribution after subcutaneous administration is 20-25 l (for a person weighing approximately 100 kg). Liraglutide is extensively bound to plasma protein (> 98 %).

Biotransformation

During 24 hours following administration of a single [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).

Elimination

Liraglutide is endogenously metabolised in a similar manner to large proteins without a specific organ as major route of elimination. Following a [3H]-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 liraglutide is approximately 0.9-1.4 l/h with an elimination half-life of approximately 13 hours.

Special populations

Elderly
Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a population pharmacokinetic analysis of data from overweight and obese patients (18 to 82 years). No dosage adjustment is required based on age.

Gender

Liraglutide STADA is indicated for the treatment of adults, adolescents and children aged 10 years and above with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance or contraindications
- 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.

Posology

To improve gastrointestinal 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.

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

Self-monitoring of blood glucose is not needed in order to adjust the dose of Liraglutide STADA.
Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Liraglutide STADA therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended.

Special populations

Elderly patients (> 65 years old)
No dose adjustment is required based on age (see section 5.2).

Renal impairment
No dose adjustment is required for patients with mild, moderate or severe renal impairment. There is no therapeutic experience in patients with end-stage renal disease, and Liraglutide STADA is therefore not recommended for use in these patients (see sections 5.1 and 5.2).

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

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

Method of administration

Liraglutide STADA is for subcutaneous use.
Liraglutide STADA must not be administered intravenously or intramuscularly.

Liraglutide STADA is administered once daily at any time, independent of meals, and can be injected 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 Liraglutide STADA is injected around the same time of the day, when the most convenient time of the day has been chosen. Injection sites should always 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.

Summary of the safety profile:

In five large long-term clinical phase 3a trials over 2 500 adult patients have received treatment with liraglutide 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. Severe 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 3a controlled trials, the LEADER trial (a long-term cardiovascular outcome trial) and spontaneous (post-marketing) reports. Frequencies for all events 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 (≥ 1/1 000 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 3a trials, the long-term cardiovascular outcome trial (LEADER) and spontaneous (post-marketing) reports

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Infections and infestations

Nasopharyngitis
Bronchitis

Immune system disorders

Anaphylacti c reactions

Metabolism and nutrition disorders

Hypoglycaemia
Anorexia
Appetite decreased
Dehydration

Nervous system disorders

Headache
Dizziness
Dysgeusia

Cardiac disorders

Increased heart rate

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare
Not known
Gastrointestinal disorders
Nausea
Diarrhoea
Vomiting
Dyspepsia
Abdominal pain upper
Constipation
Gastritis
Flatulence
Abdominal distension
Gastroesophageal reflux disease
Abdominal discomfort
Toothache
Delayed gastric emptying
Intestinal obstruction
Pancreatitis
(including necrotising pancreatitis)

Hepatobiliary disorders

Cholelithiasis
Cholecystitis

Skin and subcutaneous tissue disorder

Rash
Urticaria
Pruritus

Cutaneous amyloidosis
Renal and urinary disorders

Renal impairment
Renal failure acute

General disorders and administration site conditions

Fatigue
Injection site reactions
Malaise

Investigations

Increased lipase*
Increased amylase*

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

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 severe hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Severe 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). In the LEADER trial, severe hypoglycaemic episodes were reported at a lower rate with liraglutide vs placebo (1.0 vs 1.5 events per 100 patient years; estimated rate ratio 0.69 [0.51 to 0.93]) (see section 5.1). For patients treated with premix insulin at baseline and at least for the following 26 weeks, the rate of severe hypoglycaemia for both liraglutide and placebo was 2.2 events per 100 patient years.

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 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.

Cholelithiasis and cholecystitis
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 cholelithiasis and cholecystitis was 1.5 % and 1.1 % for liraglutide and 1.1 % and 0.7 % for placebo, respectively (see section 5.1).

Cutaneous amyloidosis
Cutaneous amyloidosis may occur at the injection site (see section 4.2).

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 liraglutide in long- term (26 weeks or longer) controlled trials. These reactions have usually been mild.

Pancreatitis
Few cases of acute pancreatitis (< 0.2 %) have been reported during long-term, controlled phase 3 clinical trials with liraglutide. 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 % for placebo, respectively (see sections 4.4 and 5.1).

Allergic reactions
Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of liraglutide.
Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of liraglutide. Few cases (0.05 %) of angioedema have been reported during all long-term clinical trials with liraglutide.

Paediatric population
Overall, frequency, type and severity of adverse reactions in adolescents and children aged 10 years and above were comparable to that observed in the adult population. Rate of confirmed hypoglycaemic 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 episode the rate was higher with liraglutide (1.82 events/patient year) compared to placebo (0.91 events/patient years). No severe hypoglycaemic episodes occurred in the liraglutide treatment group.

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.

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. Diabetic ketoacidosis has been reported in insulin-dependent patients 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 transient gastrointestinal 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 agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Acute pancreatitis

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, liraglutide

should be discontinued; if acute pancreatitis is confirmed, liraglutide should not be restarted (see sections 4.8 and 5.1).

Thyroid disease

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

Hypoglycaemia

Patients receiving liraglutide in combination with a sulfonylurea or 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 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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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 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 clinically 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 tmax 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 %; 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 ethinyloestradiol 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 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.

Paediatric Population

Interaction studies have only been performed in adults.

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 liraglutide 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, liraglutide 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.

Liraglutide 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 liraglutide is used in combination with a sulfonylurea or insulin.

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

5.
PHARMACOLOGICAL PROPERTIES

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

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 glucose- dependent 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, 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-1 receptor (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

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

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

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 (mean body weight approximately 73 kg) for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUCτ/24) reached

approximately 34 nmol/l (mean body weight approximately 76 kg). The exposure of liraglutide decreases with increasing body weight. 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 11-17 l. The mean volume of distribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively bound to plasma proteins (> 98 %).

Biotransformation

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

Following a [3H]-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.

Adults

Saxenda is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of:
- ≥ 30 kg/m² (obesity), or
- ≥ 27 kg/m² to <30 kg/m² (overweight) in the presence of at least one weight-related comorbidity such as dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea.

Treatment with Saxenda should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their initial body weight.

Adolescents (≥ 12 years)

Saxenda can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with:

• obesity (BMI corresponding to ≥ 30 kg/m2 for adults by international cut-off points)* and
• body weight above 60 kg.

Treatment with Saxenda should be discontinued and re-evaluated if patients have not lost at least 4% of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose.

*IOTF BMI cut-off points for obesity by sex between 12-18 years (see table 1), in accordance with study design of the Trial 4180, see section 5.1.

Table 1 IOTF BMI cut-off points for obesity by sex between 12–18 years

Age
(years)
BMI corresponding to 30 kg/m2 for adults by international cut-off points.
Males
Females

Posology

Adults
The starting dose is 0.6 mg once daily. The dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastro-intestinal tolerability (see table 3). If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Daily doses higher than 3.0 mg are not recommended.

Table 3 Dose escalation schedule

Dose
Weeks
Dose escalation
4 weeks
0.6 mg
1.2 mg
1.8 mg
2.4 mg
Maintenance dose
3.0 mg

Adolescents (≥ 12 years)

For adolescents from the age of 12 to below 18 years old a similar dose escalation schedule as for adults should be applied (see table 3). The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3.0 mg are not recommended.

Children (6 to <12 years)

For children from the age of 6 to below 12 years old a similar dose escalation schedule as for adults should be applied (see table 3). The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3.0 mg are not recommended.
Liraglutide in children should be initiated by a physician experienced in the management of obesity in children.

Missed doses
If a dose is missed within 12 hours from when it is usually taken, the patient should take the dose as soon as possible. If there is less than 12 hours to the next dose, the patient should not take the missed dose and resume the once-daily regimen with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose.

Patients with type 2 diabetes mellitus
Saxenda should not be used in combination with another GLP-1 receptor agonist.

When initiating Saxenda, it should be considered to reduce the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues (see section 4.4).

Special populations
Elderly (≥ 65 years old)
No dose adjustment is required based on age. Therapeutic experience in patients ≥ 75 years of age is limited and use in these patients is not recommended (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance ≥ 30 ml/min). Saxenda is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 ml/min) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Saxenda is not recommended for use in patients with severe hepatic impairment and should be used cautiously in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
No dose adjustment is required for adolescents and children from the age of 6 years and above.
The safety and efficacy of Saxenda in children below 6 years of age has not been established (see section 5.1).

Method of administration

Saxenda is for subcutaneous use only. It must not be administered intravenously or intramuscularly.

Saxenda is administered once daily at any time, independent of meals. It should be injected in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment.
However, it is preferable that Saxenda is injected around the same time of the day, when the most convenient time of the day has been chosen. Injection sites should always be rotated 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 liraglutide or to any of the excipients listed in section 6.1.

Summary of the safety profile:

Saxenda was evaluated for safety in 5 double-blind, placebo-controlled trials that enrolled 5 813 adult patients with overweight or obesity with at least one weight-related comorbidity. Overall, gastrointestinal reactions were the most frequently reported adverse reactions during treatment (67.9%) (see section ‘Description of selected adverse reactions’).

Tabulated list of adverse reactions

Table 4 lists adverse reactions reported in adults. Adverse reactions are 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions reported in adults
MedDRA system organ classes
Very common
Common
Uncommon
Rare
Not known
Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypoglycaemia*
Dehydration

Psychiatric disorders

Insomnia**

Nervous system disorders
Headache
Dizziness
Dysgeusia

Cardiac disorders

Tachycardia

Gastrointestinal disorders
Nausea
Vomiting
Diarrhoea
Constipation
Dry mouth
Dyspepsia
Gastritis
Gastro-oesophageal reflux disease
Abdominal pain upper
Flatulence
Eructation
Abdominal distension
Pancreatitis***
Delayed gastric emptying****

Intestinal obstruction†
Hepatobiliary disorders

Cholelithiasis***
Cholecystitis***

Skin and subcutaneous tissue disorders

Rash
Urticaria

Cutaneous amyloidosis
Renal and urinary disorders

Acute renal failure
Renal impairment

General disorders and administration site conditions

Injection site reactions
Asthenia
Fatigue
Malaise

Investigations

Increased lipase
Increased amylase

*Hypoglycaemia (based on self-reported symptoms by patients and not confirmed by blood glucose measurements) reported in patients without type 2 diabetes mellitus treated with Saxenda in combination with diet and exercise. Please see section ‘Description of selected adverse reactions’ for further information.
**Insomnia was mainly seen during the first 3 months of treatment.
***See section 4.4.
****From controlled phase 2, 3a and 3b clinical trials.
†ADR from post marketing sources.

Description of selected adverse reactions

Hypoglycaemia in patients without type 2 diabetes mellitus
In clinical trials in overweight or obese patients without type 2 diabetes mellitus treated with Saxenda in combination with diet and exercise, no severe hypoglycaemic events (requiring third party assistance) were reported. Symptoms of hypoglycaemic events were reported by 1.6% of patients treated with Saxenda and 1.1% of patients treated with placebo; however, these events were not confirmed by blood glucose measurements. The majority of events were mild.

Hypoglycaemia in patients with type 2 diabetes mellitus
In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with Saxenda in combination with diet and exercise, severe hypoglycaemia (requiring third party assistance) was reported by 0.7% of patients treated with Saxenda and only in patients concomitantly treated with sulfonylurea. Also, in these patients documented symptomatic hypoglycaemia was reported by 43.6% of patients treated with Saxenda and in 27.3% of patients treated with placebo. Among patients not concomitantly treated with sulfonylurea, 15.7% of patients treated with Saxenda and 7.6% of patients treated with placebo reported documented symptomatic hypoglycaemic events (defined as plasma glucose ≤ 3.9 mmol/L accompanied by symptoms).

Hypoglycaemia in patients with type 2 diabetes mellitus treated with insulin
In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with insulin and liraglutide 3.0 mg/day in combination with diet and exercise and up to 2 OADs, severe hypoglycaemia (requiring third party assistance) was reported by 1.5% of patients treated with liraglutide 3.0 mg/day.
In this trial, documented symptomatic hypoglycaemia (defined as plasma glucose ≤ 3.9 mmol/L accompanied by symptoms) was reported by 47.2% of patients treated with liraglutide 3.0 mg/day and by 51.8% of patients treated with placebo. Among patients concomitantly treated with sulfonylurea, 60.9% of patients treated with liraglutide 3.0 mg/day and 60.0% of patients treated with placebo reported documented symptomatic hypoglycaemic events.

Gastrointestinal adverse reactions
Most episodes of gastrointestinal events were mild to moderate, transient and the majority did not lead to discontinuation of therapy. The reactions usually occurred during the first weeks of treatment and diminished within a few days or weeks on continued treatment.

Patients ≥ 65 years of age may experience more gastrointestinal effects when treated with Saxenda.

Patients with mild or moderate renal impairment (creatinine clearance ≥ 30 ml/min) may experience more gastrointestinal effects when treated with Saxenda.

Acute renal failure
In patients treated with GLP-1 receptor agonists, there have been reports of acute renal failure. A majority of the reported events occurred in patients who had experienced nausea, vomiting or diarrhoea leading to volume depletion (see section 4.4).

Allergic reactions
Few cases of anaphylactic reactions with symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life threatening. If an anaphylactic reaction is suspected, liraglutide should be discontinued and treatment should not be restarted (see section 4.3).

Injection site reactions
Injection site reactions have been reported in patients treated with Saxenda. These reactions were usually mild and transitory and the majority disappeared during continued treatment.

Tachycardia
In clinical trials, tachycardia was reported in 0.6% of patients treated with Saxenda and in 0.1% of patients treated with placebo. The majority of events were mild or moderate. Events were isolated and the majority resolved during continued treatment with Saxenda.

Cutaneous amyloidosis
Cutaneous amyloidosis may occur at the injection site (see section 4.2).

Paediatric population

In a clinical trial conducted in adolescents of 12 years to less than 18 years with obesity, 125 patients were exposed to Saxenda for 56 weeks.
Overall, the frequency, type and severity of adverse reactions in the adolescents with obesity were comparable to that observed in the adult population. Vomiting occurred with a 2-fold higher frequency in adolescents compared to adults.
The percentage of patients reporting at least one episode of clinically significant hypoglycaemia was higher with liraglutide (1.6%) compared to placebo (0.8%). No severe hypoglycaemic episodes occurred in the trial.

In a clinical trial conducted in children of 6 to less than 12 years with obesity (Trial 4392), 56 patients were exposed to Saxenda for 56 weeks.

Overall, the frequency, type and severity of adverse reactions in the children with obesity were comparable to that observed in the adolescent and adult population.

Children reported more GI events in both liraglutide and placebo groups compared to adolescents and adults, with a 2-fold increase in vomiting observed in children compared to adolescents.

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.

Aspiration in association with general anaesthesia or deep sedation

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

Traceability

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

Patients with heart failure

There is no clinical 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.

Special populations

The safety and efficacy of liraglutide for weight management have not been established in patients:
- aged 75 years or more,
- treated with other products for weight management,

- with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain,
- with severe renal impairment,
- with severe hepatic impairment.
Use in these patients is not recommended (see section 4.2).
As liraglutide for weight management was not investigated in subjects with mild or moderate hepatic impairment, it should be used with caution in these patients (see sections 4.2 and 5.2).

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.

Pancreatitis

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, liraglutide should be discontinued; if acute pancreatitis is confirmed, liraglutide should not be restarted.

Cholelithiasis and cholecystitis

In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients treated with liraglutide than in patients on placebo. The fact that substantial weight loss can increase the risk of cholelithiasis and thereby cholecystitis only partially explained the higher rate with liraglutide. Cholelithiasis and cholecystitis may lead to hospitalisation and cholecystectomy. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid disease

In clinical trials in type 2 diabetes, thyroid adverse events, such as goitre, have been reported in particular in patients with pre-existing thyroid disease. Liraglutide should therefore be used with caution in patients with thyroid disease.

Heart rate

An increase in heart rate was observed with liraglutide in clinical trials (see section 5.1). Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should be informed of the symptoms of increased heart rate (palpitations or feelings of a racing heartbeat while at rest). For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with liraglutide should be discontinued.

Dehydration

Signs and symptoms of dehydration, including renal impairment and acute renal failure, have been reported in patients treated with GLP-1 receptor agonists. 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.

Hypoglycaemia in patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus receiving liraglutide in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of insulin and/or sulfonylurea.

Paediatric population

Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥ 12 years) treated with liraglutide. Patients should be informed about the characteristic symptoms of hypoglycaemia and the appropriate actions.

Hyperglycaemia in insulin treated patients with diabetes mellitus

In patients with diabetes mellitus Saxenda must not be used as a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin (see section 4.2).

Excipients

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

In vitro, liraglutide has shown very low potential to be involved in pharmacokinetic interactions with other active substances related to cytochrome P450 (CYP) 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.

Interaction studies have been performed with 1.8 mg liraglutide. The effect on rate of gastric emptying was equivalent between liraglutide 1.8 mg and 3.0 mg, (paracetamol AUC0-300 min). 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 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 International Normalised Ratio (INR) is recommended.

Paracetamol (Acetaminophen)

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 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 tmax was delayed 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.

Paediatric population

Interaction studies have only been performed in adults.

Pregnancy

There are limited 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. If a patient wishes to become pregnant or pregnancy occurs, treatment with liraglutide 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, Saxenda 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 (see section 5.3).

Saxenda has no or negligible influence on the ability to drive and use machines. However, dizziness can be experienced mainly during the first 3 months of treatment with Saxenda. Driving or use of machines should be exercised with caution if dizziness occurs.

From clinical trials and post-marketing use of liraglutide overdoses have been reported up to 72 mg (24 times the recommended dose for weight management). Events reported included severe nausea, severe vomiting and severe hypoglycaemia.

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

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

Liraglutide is an acylated human glucagon-like peptide-1 (GLP-1) analogue with 97% amino acid sequence homology to endogenous human GLP-1. Liraglutide binds to and activates the GLP-1 receptor (GLP-1R).

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

Liraglutide lowers body weight in humans mainly through loss of fat mass with relative reductions in visceral fat being greater than for subcutaneous fat loss. Liraglutide regulates appetite by increasing feelings of fullness and satiety, while lowering feelings of hunger and prospective food consumption, thereby leading to reduced food intake. Liraglutide does not increase energy expenditure compared to placebo.

Liraglutide stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner which results in a lowering of fasting and post-prandial glucose. The glucose-lowering effect is more pronounced in patients with prediabetes and diabetes compared to patients with normoglycaemia.
Clinical trials suggest that liraglutide improves and sustains beta-cell function, according to HOMA-B and the proinsulin-to-insulin ratio.

Clinical efficacy and safety

The efficacy and safety of liraglutide for weight management in conjunction with reduced calorie intake and increased physical activity were studied in four phase 3 randomised, double-blind, placebo- controlled trials which included a total of 5 358 adult patients.

- Trial 1 (SCALE Obesity & Pre-Diabetes - 1839): A total of 3 731 patients with obesity (BMI ≥ 30 kg/m²) or with overweight (BMI ≥ 27 kg/m²) with dyslipidaemia and/or hypertension were stratified according to prediabetes status at screening and BMI at baseline (≥ 30 kg/m² or < 30 kg/m²). All 3 731 patients were randomised to 56 weeks of treatment and the 2 254 patients with prediabetes at screening were randomised to 160 weeks of treatment. Both treatment periods were followed by a 12-week off drug/placebo observational follow-up period.
Lifestyle intervention in the form of an energy-restricted diet and exercise counselling was background therapy for all patients.

Absorption

The absorption of liraglutide following subcutaneous administration was slow, reaching maximum concentration approximately 11 hours post dosing. The average liraglutide steady state concentration (AUCτ/24) reached approximately 31 nmol/L in obese (BMI 30-40 kg/m2) patients following administration of 3 mg liraglutide. Liraglutide exposure increased proportionally with dose. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution

The mean apparent volume of distribution after subcutaneous administration is 20-25 L (for a person weighing approximately 100 kg). Liraglutide is extensively bound to plasma protein (> 98%).

Biotransformation

During 24 hours following administration of a single [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).

Elimination

Liraglutide is endogenously metabolised in a similar manner to large proteins without a specific organ as major route of elimination. Following a [3H]-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 liraglutide is approximately 0.9-1.4 L/h with an elimination half-life of approximately 13 hours.

Special populations

Elderly
Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a population pharmacokinetic analysis of data from overweight and obese patients (18 to 82 years). No dosage adjustment is required based on age.

Gender

Victoza is indicated for the treatment of adults, adolescents and children aged 10 years and above with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
- as monotherapy when metformin is considered inappropriate due to intolerance or contraindications
- 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.

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.

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

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

Special populations

Elderly patients (>65 years old)
No dose adjustment is required based on age (see section 5.2).

Renal impairment
No dose adjustment is required for patients with mild, moderate or severe renal impairment. There is no therapeutic experience in patients with end-stage renal disease, and Victoza is therefore not recommended for use in these patients (see sections 5.1 and 5.2).

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

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

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. Injection sites should always 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.

Summary of the safety profile

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) 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. Severe 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 3a controlled trials, the LEADER trial (a long-term cardiovascular outcome trial) and spontaneous (post-marketing) reports. Frequencies for all events 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 (≥1/1,000 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 3a trials, the long-term cardiovascular outcome trial (LEADER) and spontaneous (post-marketing) reports

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare

Not known
Infections and infestations

Nasopharyngitis
Bronchitis

Immune system disorders

Anaphylacti c reactions

Metabolism and nutrition disorders

Hypoglycaemia
Anorexia
Appetite decreased
Dehydratio n

Nervous system disorders

Headache
Dizziness
Dysgeusia

MedDRA system organ classes
Very common
Common
Uncommon
Rare
Very rare

Not known
Cardiac disorders

Increased heart rate

Gastrointesti nal disorders
Nausea
Diarrhoea
Vomiting
Dyspepsia
Abdominal pain upper
Constipation
Gastritis
Flatulence
Abdominal distension
Gastroesophage al reflux disease
Abdominal discomfort
Toothache
Delayed gastric emptying
Intestinal obstruction
Pancreatitis
(including necrotising pancreatitis)

Hepatobiliar y disorders

Cholelithias is
Cholecystiti s

Skin and subcutaneou s tissue disorder

Rash
Urticaria
Pruritus

Cutaneous amyloidosis
Renal and urinary disorders

Renal impairment
Renal failure acute

General disorders and administratio n site conditions

Fatigue
Injection site reactions
Malaise

Investigation s

Increased lipase*
Increased amylase*

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

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 severe hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Severe 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). In the LEADER trial, severe hypoglycaemic episodes were reported at a lower rate with liraglutide vs placebo (1.0 vs 1.5 events per 100 patient years; estimated rate ratio 0.69 [0.51 to 0.93]) (see section 5.1). For patients treated with premix insulin at baseline and at least for the following 26 weeks, the rate of severe hypoglycaemia for both liraglutide and placebo was 2.2 events

per 100 patient years.

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 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.

Cholelithiasis and cholecystitis
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 cholelithiasis and cholecystitis was 1.5% and 1.1% for liraglutide and 1.1% and 0.7% for placebo, respectively (see section 5.1).

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

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 long- term (26 weeks or longer) controlled trials. These reactions have usually been mild.

Pancreatitis
Few cases of acute pancreatitis (<0.2%) have been reported during long-term, controlled phase 3 clinical 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% for placebo, respectively (see sections 4.4 and 5.1).

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 angioedema have been reported during all long-term clinical trials with Victoza.

Paediatric population
Overall, frequency, type and severity of adverse reactions in adolescents and children aged 10 years and above were comparable to that observed in the adult population. Rate of confirmed hypoglycaemic 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 episode the rate was higher with liraglutide (1.82 events/patient year) compared to placebo (0.91 events/patient years). No severe hypoglycaemic episodes occurred in the liraglutide treatment group.

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.

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. Diabetic ketoacidosis has been reported in insulin-dependent patients 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 transient gastrointestinal 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 agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Acute pancreatitis

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

Thyroid disease

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

Hypoglycaemia

Patients receiving liraglutide in combination with a sulfonylurea or 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 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.

Excipients

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

Traceability

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

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 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 clinically 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 tmax 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%; 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 ethinyloestradiol 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 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.

Paediatric Population

Interaction studies have only been performed in adults.

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.

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 insulin.

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

5.
PHARMACOLOGICAL PROPERTIES

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

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 glucose- dependent 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, 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-1 receptor (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

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

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

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 (mean body weight approximately 73 kg) for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUCτ/24) reached approximately 34 nmol/l (mean body weight approximately 76 kg). The exposure of liraglutide decreases with increasing body weight. 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 11–17 l. The mean volume of distribution after intravenous administration of liraglutide is 0.07 l/kg. Liraglutide is extensively bound to plasma proteins (>98%).

Biotransformation

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

Following a [3H]-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.