- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyTo 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.Victoza can be added to existing metformin or to a combination of metformin and thiazolidinedione therapy. The current dose of metformin and thiazolidinedione can be continued unchanged.Victoza can be added to existing sulfonylurea or to a combination of metformin and sulfonylurea therapy or a basal insulin. When Victoza is added to sulfonylurea therapy or basal insulin, a reduction in the dose of sulfonylurea or basal insulin should be considered to reduce the risk of hypoglycaemia (see section 4.4).Self-monitoring of blood glucose is not needed in order to adjust the dose of Victoza. However, when initiating treatment with Victoza in combination with a sulfonylurea or a basal insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulfonylurea or the basal insulin.
Elderly patients (>65 years old)No dose adjustment is required based on age. Therapeutic experience in patients ≥75 years of age is limited (see section 5.2).
Patients with renal impairmentNo dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance 6090 ml/min and 3059 ml/min, respectively). There is no therapeutic experience in patients with severe renal impairment (creatinine clearance below 30 ml/min). Victoza can currently not be recommended for use in patients with severe renal impairment including patients with end-stage renal disease (see section 5.2).
Patients with hepatic impairmentThe therapeutic experience in patients with all degrees of hepatic impairment is currently too limited to recommend the use in patients with mild, moderate or severe hepatic impairment (see section 5.2).
Paediatric populationThe safety and efficacy of Victoza in children and adolescents below age 18 have not been established (see section 5.1). No data are available.
Method of administrationVictoza 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. For further instructions on administration, see section 6.6.
Acute pancreatitisUse of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. There have been few reported events of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Victoza should be discontinued; if acute pancreatitis is confirmed, Victoza should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Thyroid diseaseThyroid adverse events, including increased blood calcitonin, goitre and thyroid neoplasm have been reported in clinical trials in particular in patients with pre-existing thyroid disease and liraglutide should therefore be used with caution.
HypoglycaemiaPatients receiving liraglutide in combination with a sulfonylurea or a basal 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 basal insulin.
DehydrationSigns 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.
Warfarin and other coumarin derivativesNo 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.
ParacetamolLiraglutide 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.
AtorvastatinLiraglutide 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.
GriseofulvinLiraglutide 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.
DigoxinA 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.
LisinoprilA 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 contraceptivesLiraglutide 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.
InsulinNo 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.
PregnancyThere 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-feedingIt 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.
FertilityApart from a slight decrease in the number of live implants, animal studies did not indicate harmful effects with respect to fertility.
Summary of the safety profileIn five large long-term clinical trials over 2,500 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. Major hypoglycaemia has primarily been observed when combined with a sulfonylurea.
Tabulated list of adverse reactionsTable 1 lists adverse reactions reported in long term phase 3 controlled trials and spontaneous (postmarketing) reports. Frequencies for related spontaneous reports (postmarketing) have been calculated based on their incidence in phase 3 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 3 trials and spontaneous (postmarketing) reports
|MedDRAsystem organ classes||Very common||Common||Uncommon||Rare||Very rare|
|Infections and infestations||Nasopharyngitis Bronchitis|
|Immune system disorders||Anaphylactic reactions|
|Metabolism and nutrition disorders||Hypoglycaemia Anorexia Appetite decreased||Dehydration|
|Nervous system disorders||Headache Dizziness|
|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||Intestinal obstruction||Pancreatitis (including necrotising pancreatitis)|
|Skin and subcutaneous tissue disorder||Rash||Urticaria Pruritus|
|Renal and urinary disorders||Renal impairment Renal failure acute|
|General disorders and administration site conditions||Fatigue Injection site reactions||Malaise|
Description of selected adverse reactionsIn 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.
HypoglycaemiaMost episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of major hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Major 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).
Gastrointestinal adverse reactionsWhen 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 3059 ml/min, respectively) may experience more gastrointestinal effects when treated with liraglutide.
WithdrawalThe 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 reactionsInjection 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.
PancreatitisFew cases (<0.2%) of acute pancreatitis have been reported during long-term clinical trials with Victoza. Pancreatitis was also reported post-marketing.
Allergic reactionsAllergic 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.
Reporting of suspected adverse reactionsReporting 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:
United KingdomYellow Card SchemeWebsite: www://yellowcard.mhra.gov.uk
IrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.iee-mail: firstname.lastname@example.org
Mechanism of actionLiraglutide 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-1R, increased key satiety and decreased key hunger signals, thereby leading to lower body weight.
Pharmacodynamic effectsLiraglutide 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 safetyFive double-blind, randomised, controlled clinical trials were conducted to evaluate the effects of liraglutide on glycaemic control (Table 2-5). Treatment with liraglutide produced clinically and statistically significant improvements in glycosylated haemoglobin A1c (HbA1c), fasting plasma glucose and postprandial glucose compared with placebo.These trials included 3,978 exposed patients with type 2 diabetes (2,501 patients treated with Victoza), 53.7% men and 46.3% women, 797 patients (508 treated with liraglutide) were ≥65 years of age and 113 patients (66 treated with liraglutide) were ≥75 years of age.Additional trials were conducted with liraglutide that included 1,901 patients in four unblinded randomised, controlled clinical trials (including 464, 658, 323 and 177 subjects per trial) and one double-blind, randomised, controlled clinical trial in subjects with type 2 diabetes and moderate renal impairment (279 patients). Glycaemic control
Combination with oral antidiabeticsLiraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA1c compared with patients receiving placebo (Tables 2 to 5).
Combination with metformin
Table 2 Victoza in combination with metformin (26 weeks)
|Metformin add-on therapy||1.8 mg liraglutide + metformin2||1.2 mg liraglutide + metformin2||Placebo + metformin2||Glimepiride1 + metformin2|
|Mean HbA1c (%) Baseline Change from baseline||8.4 -1.00||8.3 -0.97||8.4 0.09||8.4 -0.98|
|Patients (%) achieving HbA1c <7% All patients Previous OAD monotherapy||42.4 66.3||35.3 52.8||10.8 22.5||36.3 56.0|
|Mean body weight (kg) Baseline Change from baseline||88.0 -2.79||88.5 -2.58||91.0 -1.51||89.0 0.95|
Combination with sulfonylurea
Table 3 Victoza in combination with glimepiride (26 weeks)
|Glimepiride add-on therapy||1.8 mg liraglutide + glimepiride2||1.2 mg liraglutide + glimepiride2||Placebo + glimepiride2||Rosiglitazone1 + glimepiride2|
|Mean HbA1c (%) Baseline Change from baseline||8.5 -1.13||8.5 -1.08||8.4 0.23||8.4 -0.44|
|Patients (%) achieving HbA1c <7% All patients Previous OAD monotherapy||41.6 55.9||34.5 57.4||7.5 11.8||21.9 36.1|
|Mean body weight (kg) Baseline Change from baseline||83.0 -0.23||80.0 0.32||81.9 -0.10||80.6 2.11|
Combination with thiazolidinedione and metformin
Table 4 Victoza in combination with metformin + rosiglitazone (26 weeks)
|Metformin + rosiglitazone add-on therapy||1.8 mg liraglutide + metformin1 + rosiglitazone2||1.2 mg liraglutide + metformin1 + rosiglitazone2||Placebo + metformin1 + rosiglitazone2||N/A|
|Mean HbA1c (%) Baseline Change from baseline||8.56 -1.48||8.48 -1.48||8.42 -0.54|
|Patients (%) achieving HbA1c <7% All patients||53.7||57.5||28.1|
|Mean body weight (kg) Baseline Change from baseline||94.9 -2.02||95.3 -1.02||98.5 0.60|
Combination with sulfonylurea and metformin
Table 5 Victoza in combination with glimepiride + metformin (26 weeks)
|Metformin + glimepiride add-on therapy||1.8 mg liraglutide + metformin2 + glimepiride3||N/A||Placebo + metformin2 + glimepiride3||Insulin glargine1 + metformin2 + glimepiride3|
|Mean HbA1c (%) Baseline Change from baseline||8.3 -1.33||8.3 -0.24||8.1 -1.09|
|Patients (%) achieving HbA1c <7% All patients||53.1||15.3||45.8|
|Mean body weight (kg) Baseline Change from baseline||85.8 -1.81||85.4 -0.42||85.2 1.62|
Guideline for titration of insulin glargine
|Self-measured FPG||Increase in insulin glargine dose (IU)|
|≤5.5 mmol/l (≤100 mg/dl) Target||No adjustment|
|>5.5 and <6.7 mmol/l (>100 and <120 mg/dl)||02 IUa|
|≥6.7 mmol/l (≥120 mg/dl)||2 IU|
Combination with insulinIn a 104-week clinical trial, 57% of patients with type 2 diabetes treated with insulin degludec in combination with metformin achieved a target HbA1c <7% and the remaining patients continued in a 26-week open label trial and were randomised to add liraglutide or a single dose of insulin aspart (with the largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% in order to minimize the risk of hypoglycaemia. Addition of liraglutide resulted in a statistically significantly greater reduction of HbA1c (-0.73% for liraglutide vs -0.40% for comparator) and body weight (-3.03 vs 0.72 kg). The rate of hypoglycaemic episodes (per patient year of exposure) was statistically significantly lower when adding liraglutide compared to adding a single dose of insulin aspart (1.0 vs 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21). In a 52-week clinical trial, the addition of insulin detemir to liraglutide 1.8 mg and metformin in patients not achieving glycaemic targets on liraglutide and metformin alone resulted in a HbA1c decrease from baseline of 0.54%, compared to 0.20% in the liraglutide 1.8 mg and metformin control group. Weight loss was sustained. There was a small increase in the rate of minor hypoglycaemic episodes (0.23 versus 0.03 events per patient years).
Use in patients with renal impairmentIn a double-blind trial comparing the efficacy and safety of liraglutide 1.8 mg versus placebo as add-on to insulin and/or OAD in patients with type 2 diabetes and moderate renal impairment, liraglutide was superior to placebo treatment in reducing HbA1c after 26 weeks (1.05% vs 0.38%). Significantly more patients achieved HbA1c below 7% with liraglutide compared with placebo (52.8% vs 19.5%). In both groups a decrease in body weight was seen: 2.4 kg with liraglutide vs 1.09 kg with placebo. There was a comparable risk of hypoglycaemic episodes between the two treatment groups. The safety profile of liraglutide was generally similar to that observed in other studies with liraglutide. Proportion of patients achieving reductions in HbA1cLiraglutide in combination with metformin, glimepiride, or metformin and rosiglitazone resulted in a statistically significant (p≤0.0001) greater proportion of patients achieving an HbA1c ≤6.5% at 26 weeks compared with patients receiving these agents alone. Fasting plasma glucoseTreatment with liraglutide alone or in combination with one or two oral antidiabetic drugs resulted in a reduction in fasting plasma glucose of 13-43.5 mg/dl (0.72-2.42 mmol/l). This reduction was observed within the first two weeks of treatment. Postprandial glucoseLiraglutide reduces postprandial glucose across all three daily meals by 31-49 mg/dl (1.68-2.71 mmol/l). Beta-cell functionClinical trials with liraglutide indicate improved beta-cell function based on measures such as the homeostasis model assessment for beta-cell function (HOMA-B) and the proinsulin to insulin ratio. Improved first and second phase insulin secretion after 52 weeks treatment with liraglutide was demonstrated in a subset of patients with type 2 diabetes (N=29). Body weightLiraglutide in combination with metformin, metformin and glimepiride or metformin and rosiglitazone was associated with sustained weight reduction over the duration of trials in a range from 1.0 kg to 2.8 kg.Larger weight reduction was observed with increasing body mass index (BMI) at baseline. Cardiovascular evaluation
Blood pressureOver the duration of the trials, liraglutide decreased the systolic blood pressure on average of 2.3 to 6.7 mmHg from baseline and compared to active comparator the decrease was 1.9 to 4.5 mmHg.Post-hoc analysis of serious major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) from all intermediate and long-term phase 2 and 3 trials (ranging from 26 and up to 100 weeks duration) including 5,607 patients (3,651 exposed to liraglutide), showed no increase in cardiovascular risk (incidence ratio of 0.75 (95% CI 0.35; 1.63) for the composite endpoint for liraglutide versus all comparators (metformin, glimepiride, rosiglitazone, insulin glargine, placebo)). High-risk cardiovascular patients were excluded from the trials and the incidence rates of serious major cardiovascular events in the trials were low (6.02 per 1,000 patient years in liraglutide-treated patients and 10.45 in all-comparator-treated patients), precluding firm conclusions.
ImmunogenicityConsistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-liraglutide antibodies following treatment with liraglutide. On average, 8.6% of patients developed antibodies. Antibody formation has not been associated with reduced efficacy of liraglutide.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies with Victoza in one or more subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
Other clinical dataIn an open label trial comparing the efficacy and safety of liraglutide (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA1c 8.5%), liraglutide at both doses was statistically superior to sitagliptin treatment in reducing HbA1c after 26 weeks (-1.24%, -1.50% vs -0.90%, p<0.0001). Patients treated with liraglutide had a significant decrease in body weight compared to that of patients treated with sitagliptin (-2.9 kg and -3.4 kg vs -1.0 kg, p<0.0001). Greater proportions of patients treated with liraglutide experienced transient nausea vs patients treated with sitagliptin (20.8% and 27.1% for liraglutide vs. 4.6% for sitagliptin). The reductions in HbA1c and superiority vs sitagliptin observed after 26 weeks of liraglutide treatment (1.2 mg and 1.8 mg) were sustained after 52 weeks of treatment (-1.29% and -1.51% vs -0.88%, p<0.0001). Switching patients from sitagliptin to liraglutide after 52 weeks of treatment resulted in additional and statistically significant reduction in HbA1c (-0.24% and -0.45%, 95% CI: -0.41 to -0.07 and -0.67 to -0.23 ) at week 78, but a formal control group was not available.In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg once daily and exenatide 10 mcg twice daily in patients inadequately controlled on metformin and/or sulfonylurea therapy (mean HbA1c 8.3%), liraglutide was statistically superior to exenatide treatment in reducing HbA1c after 26 weeks (-1.12% vs -0.79%; estimated treatment difference: -0.33; 95% CI: -0.47 to -0.18). Significantly more patients achieved HbA1c below 7% with liraglutide compared with exenatide (54.2% vs 43.4%, p=0.0015). Both treatments resulted in mean body weight loss of approximately 3 kg. Switching patients from exenatide to liraglutide after 26 weeks of treatment resulted in an additional and statistically significant reduction in HbA1c (-0.32%, 95% CI: -0.41 to -0.24) at week 40, but a formal control group was not available. During the 26 weeks, there were 12 serious events in 235 patients (5.1%) using liraglutide, whereas there were 6 serious adverse events in 232 patients (2.6%) using exenatide. There was no consistent pattern with respect to system organ class of events.
AbsorptionThe 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 for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUC/24) reached approximately 34 nmol/l. 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%.
DistributionThe 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%).
BiotransformationDuring 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.
EliminationFollowing 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 a single dose liraglutide is approximately 1.2 l/h with an elimination half-life of approximately 13 hours.
Special populationsElderly patients:Age had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results from a pharmacokinetic study in healthy subjects and population pharmacokinetic data analysis of patients (18 to 80 years).Gender:Gender had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of male and female patients and a pharmacokinetic study in healthy subjects.
Ethnic origin:Ethnic origin had no clinically relevant effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analysis which included patients of White, Black, Asian and Hispanic groups.Obesity:Population pharmacokinetic analysis suggests that body mass index (BMI) has no significant effect on the pharmacokinetics of liraglutide.
Hepatic impairment:The pharmacokinetics of liraglutide was evaluated in patients with varying degree of hepatic impairment in a single-dose trial. Liraglutide exposure was decreased by 13-23% in patients with mild to moderate hepatic impairment compared to healthy subjects.Exposure was significantly lower (44%) in patients with severe hepatic impairment (Child Pugh score >9).
Renal impairment:Liraglutide exposure was reduced in patients with renal impairment compared to individuals with normal renal function. Liraglutide exposure was lowered by 33%, 14%, 27% and 28%, respectively, in patients with mild (creatinine clearance, CrCl 50-80 ml/min), moderate (CrCl 30-50 ml/min), and severe (CrCl <30 ml/min) renal impairment and in end-stage renal disease requiring dialysis. Similarly, in a 26-week clinical trial, patients with type 2 diabetes and moderate renal impairment (CrCL 30-59 ml/min, see section 5.1) had 26% lower liraglutide exposure when compared with a separate trial including patients with type 2 diabetes with normal renal function or mild renal impairment.
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