4.1. Therapeutic indications

Liraglutide Zentiva 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.

4.2. Posology and method of administration

Posology

To improve gastro-intestinal tolerability, the starting dose is 0.6 mg liraglutide daily. After at least one week, the dose should be increased to 1.2 mg. Some patients are expected to benefit from an increase in dose from 1.2 mg to 1.8 mg and based on clinical response, after at least one week, the dose can be increased to 1.8 mg to further improve glycaemic control. Daily doses higher than 1.8 mg are not recommended.

When liraglutide 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 .

Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when liraglutide 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 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 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 must not be administered intravenously or intramuscularly.

Liraglutide 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 liraglutide 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 the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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

Liraglutide is not a substitute for insulin. 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.

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 (see sections 4.8 and 5.1).

Thyroid disease

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.

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.

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 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

Liraglutide 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 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of liraglutide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Liraglutide should not be used during pregnancy, and the use of insulin is recommended instead. If a patient wishes to become pregnant, or pregnancy occurs, treatment with 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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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

Anaphylactic reactions

Metabolism and nutrition disorders

Hypoglycaemia

Anorexia

Appetite decreased

Dehydration

Nervous system disorders

Headache

Dizziness

Dysgeusia

Cardiac disorders

Increased heart rate

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 disorders

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 Yellow Card Scheme Website: 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 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.