4.1. Therapeutic indications

Adults

Nevolat 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 (pre-diabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia or obstructive sleep apnoea.

Treatment with Nevolat 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)

Nevolat 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 Nevolat 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):

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

12

26.02

26.67

12.5

26.43

27.24

13

26.84

27.76

13.5

27.25

28.20

14

27.63

28.57

14.5

27.98

28.87

15

28.30

29.11

15.5

28.60

29.29

16

28.88

29.43

16.5

29.14

29.56

17

29.41

29.69

17.5

29.70

29.84

18

30.00

30.00

4.2. Posology and method of administration

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 2). 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 2 Dose escalation schedule

Dose

Weeks

Dose escalation 4 weeks

0.6 mg

1

1.2 mg

1

1.8 mg

1

2.4 mg

1

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 2). 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.

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

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

When initiating Nevolat, 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). Nevolat 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. Nevolat 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 from the age of 12 years and above.

The safety and efficacy of Nevolat in children below 12 years of age has not been established (see section 5.1).

Method of administration

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

Nevolat 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 Nevolat 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 4.8).

For further instructions on administration, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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.

Acute pancreatitis

Liraglutide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.

Acute pancreatitis has been reported in patients treated with GLP-1 receptor agonists. This includes post-marketing reports of necrotising pancreatitis and reports with a fatal outcome. Patients should be informed of the symptoms of acute pancreatitis, including persistent, severe abdominal pain. Patients should be advised to seek immediate medical attention if they occur. If pancreatitis is suspected, liraglutide should be discontinued; if the diagnosis of pancreatitis is confirmed, liraglutide should not be restarted.

In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.

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.

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.

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 Nevolat 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

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

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

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, Nevolat 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).

4.7. Effects on ability to drive and use machines

Nevolat 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 Nevolat. Driving or use of machines should be exercised with caution if dizziness occurs.

4.8. Undesirable effects

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 3 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 3 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

Diarrhoea

Vomiting

Constipation

Dry mouth

Dyspepsia

Gastritis

Gastroesophageal 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.

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 Yellow Card Scheme Website at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.