Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
Hypersensitivity to liraglutide or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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.
The safety and efficacy of liraglutide for weight management have not been established in patients:
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 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.
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.
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.
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.
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.
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.
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.
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).
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 AUC~0-300 min~). Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicinal products.
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 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.
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.
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.
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.
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.
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.
Interaction studies have only been performed in adults
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.
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.
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.
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’).
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). 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 |
|---|---|---|---|---|
| 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**** | |
| Hepatobiliary disorders | Cholelithiasis*** | Cholecystitis*** | ||
| Skin and subcutaneous tissue disorders | Urticaria | |||
| 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.
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.
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).
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.
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.
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).
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 have been reported in patients treated with Saxenda. These reactions were usually mild and transitory and the majority disappeared during continued treatment.
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.
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.
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.
Substances added to Saxenda may cause degradation of liraglutide. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
