Liraglutide

No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Liraglutide is not recommended for use in patients with severe hepatic impairment and should be used cautiously in patients with mild or moderate hepatic impairment.

Liraglutide is not recommended for use in patients with severe renal impairment (creatinine clearance <30 ml/min) including patients with end-stage renal disease.

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.

Patients receiving liraglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered by a reduction in the dose of sulfonylurea or insulin.

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.

Liraglutide lowered ethinylestradiol and levonorgestrel C_max by 12% and 13%, respectively, following administration of a single dose of an oral contraceptive product. t_max was delayed by 1.5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with liraglutide.

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

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 C_max was decreased by 38% and median t_max was delayed from 1 h to 3 h with liraglutide.

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

Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin C_max increased by 37% while median t_max did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril AUC by 15%; C_max decreased by 27%. Lisinopril median t_max was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.

Liraglutide did not change the overall exposure of paracetamol following a single dose of 1,000 mg. Paracetamol C_max was decreased by 31% and median tmax was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.

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.

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.

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

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 should be considered prior to performing procedures with general anaesthesia or deep sedation.

There are limited data from the use of liraglutide in pregnant women. Studies in animals have shown reproductive toxicity. 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.

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. 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. 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.

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.

Insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise

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:

^* 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). 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]). 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.

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 longterm (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.

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.

Weight management

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 2 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2. Adverse reactions reported in adults:

^* 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.
^*** 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.

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.

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.

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.