Victoza 6 mg/ml solution for injection in pre-filled pen

Section 4.2: Addition of a sentence advising the rotation of injection sites to reduce the risk of amyloid deposits.

Section 4.8: Addition of Cutaneous amyloidosis as an adverse reaction with a frequency of ‘Not known’

Section 3: Addition of a sentence advising the rotation of injection sites to reduce the risk of lumps.

Section 4: Addition of Cutaneous amyloidosis as an adverse reaction with a frequency of ‘Not known’

Change to section 4.4 - Addition of text:

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.

Section 2 - Warnings and precautions - Addition of:

If you know that you are due to have surgery where you will be under anesthesia (sleeping), please tell your doctor that you are taking Victoza®.

Section 4 - Reporting of side effects - Deletion of:

United Kingdom (Northern Ireland)

Yellow Card Scheme

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

Addition to undesirable effects section 4.8 : Dysgeusia

Addition to side effects section: Change in how things taste

United Kingdom updated to United Kingdom (Northern Ireland)

Date of revision updated to 07/2022

No content changes. 

Section 4.4:

Addition of:

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Section 4.9

Updated to:

From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the recommended maintenance dose. Events Generally, the patients  reported included severe nausea, vomiting, and diarrhoea and severe hypoglycaemia. None of the patients reported severe hyopglycaemia. All patients recovered without complications.

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.

Section 3:

If you use more Victoza® than you should

If you use more Victoza® than you should, talk to your doctor straight away. You may need medical treatment. You may experience nausea, vomiting, or diarrhoea or low blood sugar (hypoglycaemia).  Please refer to section 4 for warning signs of low blood sugar.

Section 4.4:

Addition of:

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Section 4.9

Updated to:

From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the recommended maintenance dose. Events Generally, the patients  reported included severe nausea, vomiting, and diarrhoea and severe hypoglycaemia. None of the patients reported severe hyopglycaemia. All patients recovered without complications.

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.

Section 4 - Possible side effects

Addition of 'a delay in the emptying of the stomach' as an uncommon side effect

Section 4 - how to report a side effect

Updated to simplified contact details for HPRA

Section 6

revision date updated to '10/2019'

Section 4.8:

Addition of 'Delayed gastric emptying' as an uncommon side effect

Section 4.8 - how to report a side effect:

Updated to simplified contact details for HPRA

Section 10:

revision date updated to '10/2019'

Section 4.1:

 Therapeutic indication expanded to include “adolescents and children aged 10 years and above”

Section 4.2:

Text deleted: “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 insulin.”

Text added: “Combination therapy with sulfonylurea is only valid for adult patients.”

Paediatric population text updated as follows:

“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). “

 “The safety and efficacy of Victoza in children and adolescents below age 18 have not been established (see section 5.1). No data are available.”

Section 4.4:

Text added:

“Excipients: Victoza contains less than 1 mmol sodium (23 mg) per dose, therefore the medicinal product is essentially ‘sodium-free’.”

Section 4.5:

Text added:

“Paediatric Population

Interaction studies have only been performed in adults.”

Section 4.8

Text added:

“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. “

Section 5.1

Text updated:

Combination with oral antidiabetics

Liraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone or SGLT2i ± metformin resulted in statistically significant and sustained reductions in HbA_1c compared with patients receiving placebo (Table 2).

Table 2 updated

Table 2 updated to include information regarding “Add-on to SGLT2i⁵ ± metformin (≥1500 mg/day)”

^***Superiority (p<0.001) vs active comparator

⁵Victoza add-on to SGLT2i was investigated at all approved doses of SGLT2i

Text updated:

•             Proportion of patients achieving reductions in HbA_1c

… Liraglutide in combination with metformin, glimepiride, or metformin and rosiglitazone or SGLT2i ± metformin resulted in a statistically significant greater proportion of patients achieving an HbA_1c ≤6.5% at 26 weeks compared with patients receiving these agents alone.

•             Body weight

Treatment with liraglutide alone and in combination with metformin, metformin and glimepiride,  or metformin and rosiglitazone or SGLT2i with or without metformin was associated with a sustained weight reduction over the duration of trials in the range from 0.86 1.0 kg to 2.62 2.8 kg compared with placebo.

Text updated:

Paediatric population

“In a double-blind study comparing the efficacy and safety of Victoza 1.8 mg versus placebo as add-on to metformin ± insulin in adolescents and children aged 10 years and above with type 2 diabetes, Victoza was superior to placebo treatment in reducing HbA_1c after 26 weeks (-1.06, [-1.65, 0.46]). The treatment difference in HbA_1c was 1.3% after additional 26 weeks of open label extension, confirming the sustained glycaemic control with Victoza.

 The efficacy and safety profile of Victoza was comparable to that observed in the adult population treated with Victoza. Based on adequate glycaemic control or tolerability, 30% of trial subjects remained on a dose of 0.6 mg, 17% escalated to a dose of 1.2 mg and 53% escalated to a dose of 1.8 mg.”
 

“The 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).”

Section 5.2

Text updated:

“Absorption

The 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 (mean body weight approximately 73 kg) for a subcutaneous single dose of liraglutide 0.6 mg. At 1.8 mg liraglutide, the average steady state concentration of liraglutide (AUC_τ/24) reached approximately 34 nmol/l (mean body weight approximately 76 kg). The exposure of liraglutide decreases with increasing body weight. 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%.”

New section:

“Paediatric population

Pharmacokinetic properties were assessed in clinical studies in the paediatric population with type 2 diabetes aged 10 years and above. The liraglutide exposure in adolescents and children was comparable to that observed in the adult population.”

Section 5.3:

Section deleted:

“Following intra-arterial injection of liraglutide to rabbits, slight to moderate haemorrhage, erythema and swelling at the injection site were observed.

4.1     Therapeutic indications

Victoza is indicated for the treatment of adults with insufficientlytype 2 diabetes mellitus to achieve glycaemic controlled type 2 diabetes mellitus as an adjunct to diet and exercise

•        as:

Mmonotherapy

W when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of 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.

Combination therapy

In combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations).

4.2     Posology and method of administration

Posology

Special populations

Thyroid disease

Thyroid adverse events, including increased blood calcitonin,such as goitre, and thyroid neoplasm have been reported in clinical trials, and in particular in patients with pre-­existing thyroid disease. and liraglutideLiraglutide should therefore be used with caution in these patients.

4.5     Interaction with other medicinal products and other forms of interaction

4.8     Undesirable effects

Summary of the safety profile

In five large long-term clinical phase 3a 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. SevereMajor 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 eventsrelated spontaneous reports (postmarketing) 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

ypoglycaemia

Most episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of majorsevere hypoglycaemia were observed in the trial with liraglutide used as monotherapy. SevereMajor 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.

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).

Pancreatitis

Few cases of acute pancreatitis (<0.2%) of acute pancreatitis have been reported during long-term, controlled clinical phase 3 clinical trials with Victoza. Pancreatitis was also reported frompost- marketeding 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).

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analoguesother blood glucose lowering drugs, excl. insulins. ATC code: A10BJ02A10BX07

GLP-1 receptors are also expressed in specific locations in the heart, vasculature, immune system, and kidneys. In mouse models of atherosclerosis, liraglutide prevented aortic plaque progression and reduced inflammation in the plaque. In addition, liraglutide had a beneficial effect on plasma lipids. Liraglutide did not reduce the plaque size of already established plaques.

Clinical efficacy and safety

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.

Five double-blind, randomised, controlled clinical phase 3a trials were conducted to evaluate the effects of liraglutide on glycaemic control (Table 2). Treatment with liraglutide produced clinically and statistically significant improvements in glycosylated haemoglobin A_1c (HbA_1c), fasting plasma glucose and postprandial glucose compared with placebo.

These trials included 3,978 exposed patients with type 2 diabetes mellitus (2,501 patients treated with liraglutide), 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 patientssubjects per trial) and one double-blind, randomised, controlled clinical trial in patientssubjects with type 2 diabetes mellitus and moderate renal impairment (279 patients).

A large cardiovascular outcomes trial (the LEADER trial) was also conducted with liraglutide in 9,340 patients with type 2 diabetes mellitus at high cardiovascular risk.

Table 2       Liraglutide clinical phase 3a trials in monotherapy (52 weeks) and in combination with oral antidiabetics (26 weeks)

^*In the LEADER trial, (see subsection Cardiovascular evaluation), 873 patients were on premix insulin (with or without OAD(s)) at baseline and at least for the following 26 weeks. The mean HbA_1c at baseline was 8.7% for liraglutide and placebo. At week 26, the estimated mean change in HbA_1c was ‑1.4% and -0.5% for liraglutide and placebo, respectively, with an estimated treatment difference of ‑0.9 [-1.00; -0.70]_{95% CI}. The safety profile of liraglutide in combination with premix insulin was overall comparable to that observed for placebo in combination with premix insulin (see section 4.8).

•        Cardiovascular evaluation

Blood pressure

Over 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.

The Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results (LEADER) trial, was a multicentre, placebo-controlled, double-blind clinical trial. 9,340 patients were randomly allocated to either liraglutide (4,668) or placebo (4,672), both in addition to standards of care for HbA_1c and cardiovascular (CV) risk factors. Primary outcome or vital status at end of trial was available for 99.7% and 99.6% of participants randomised to liraglutide and placebo, respectively. The duration of observation was minimum 3.5 years and up to a maximum of 5 years. The study population included patients ≥65 years (n=4,329) and ≥75 years (n=836) and patients with mild (n=3,907), moderate (n=1,934) or severe (n=224) renal impairment. The mean age was 64 years and the mean BMI was 32.5 kg/m². The mean duration of diabetes was 12.8 years.

The primary endpoint was the time from randomisation to first occurrence of any major adverse cardiovascular events (MACE): CV death, non-fatal myocardial infarction or non-fatal stroke. Liraglutide was superior in preventing MACE vs placebo (Figure 1). The estimated hazard ratio was consistently below 1 for all 3 MACE components.

Liraglutide also significantly reduced the risk of expanded MACE (primary MACE, unstable angina pectoris leading to hospitalisation, coronary revascularisation, or hospitalisation due to heart failure) and other secondary endpoints (Figure 2).

Figure 1: Kaplan Meier plot of time to first MACE – FAS population

Figure 2: Forest plot of analyses of individual cardiovascular event types – FAS population

A significant and sustained reduction in HbA_1c from baseline to month 36 was observed with liraglutide vs placebo, in addition to standard of care (-1.16% vs -0.77%; estimated treatment difference [ETD] -0.40% [-0.45; -0.34]). The need for treatment intensification with insulin was reduced by 48% with liraglutide vs placebo in insulin-naive patients at baseline (HR 0.52 [0.48; 0.57]).

•        Blood pressure and heart rate

Over the duration of the phase 3a 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.

A mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed with liraglutide in long-term clinical trials including LEADER. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed.

•        Microvascular evaluation

In the LEADER trial, microvascular events comprised nephropathy and retinopathy outcomes. The analysis of time to first microvascular event for liraglutide vs placebo had a HR of 0.84 [0.73, 0.97]. The HR for liraglutide vs placebo was 0.78 [0.67, 0.92] for time to first nephropathy event and 1.15 [0.87, 1.52] for time to first retinopathy event.

6.5     Nature and contents of container

Cartridge (type 1 glass) with a plunger (bromobutyl) and a stopperlaminate rubber sheet (bromobutyl/polyisoprene) contained in a pre-filled multidose disposable pen made of polyolefin and polyacetal.

10.     DATE OF REVISION OF THE TEXT

07/2017

The following sections of the SmPC have been updated:


2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

One 1 ml of solution contains 6 mg of liraglutide*. One pre­filled pen contains 18 mg liraglutide in 3 ml.

 ...

            4.8       Undesirable effects

...

Table 1           Adverse reactions from long-term controlled phase 3 trials and spontaneous (postmarketing) reports

* From controlled phase 3b and 4 clinical trials only where they were measured.

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

 Date of first authorisation: 30 June /06/2009

Date of last renewal: 11 April /04/2014

10.       DATE OF REVISION OF THE TEXT

 05/201609/2016

The SmPC has had updates in the following sections:

• 4.1. with additional text for Monotherapy administration
• 4.2 for use in patients with mild or moderate hepatic impairment
• 5.1 with addition of Monotherapy results for HbA_1c and for Proportion of Patients achieving reductions in HbA_1c
• 5.1 with merging of tables 2-5 into table 2

Track change details below:

4.1       Therapeutic indications

Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control as:

Monotherapy

When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance or contraindications.

Combination therapy

 Iin combination with oral glucose-lowering medicinal products and/or basal insulin when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1 for available data on the different combinations).

4.2       Posology and method of administration

….

Hepatic impairment

The 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 impairmentNo dose adjustment is required for patients with hepatic impairmentNo dose adjustment is recommended for patients with mild or moderate hepatic impairment. Victoza is not recommended for use in patients with severe hepatic impairment  (see section 5.2).

5.1       Pharmacodynamic properties

…

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-1 receptorR (GLP-1R), increased key satiety and decreased key hunger signals, thereby leading to lower body weight.

….

Clinical efficacy and safety

….

These trials included 3,978 exposed patients with type 2 diabetes (2,501 patients treated with Victozaliraglutide), 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.

….

 •          Glycaemic control

Monotherapy

Liraglutide monotherapy for 52 weeks resulted in statistically significant and sustained reductions in HbA_1c for both 1.2 mg and 1.8 mg (p=0.0014, p<0.0001, respectively)compared with glimepiride 8 mg (-0.84% for 1.2 mg, -1.14% for 1.8 mg vs -0.51% for comparator) in patients previously treated with either diet and exercise or OAD monotherapy at no more than half-maximal dose (Table 2).

Combination with oral antidiabetics

Liraglutide in combination therapy, for 26 weeks, with metformin, glimepiride or metformin and rosiglitazone resulted in statistically significant (p<0.0001) and sustained reductions in HbA_1c compared with patients receiving placebo (Tables 2to 5).

Combination with metformin

Table 2            Victoza^® Liraglutide in monotherapy (52 weeks) and in combination with oral antidiabetics

(26 weeks)

4.         CLINICAL PARTICULARS

4.2       Posology and method of administration

Patients with rRenal impairment

No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance 60–90 ml/min and 30–59 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 end­stage renal disease (see section 5.2).

Patients with hHepatic impairment

The 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).

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Other clinical data

In an open label trial comparing the efficacy and safety of liraglutide 1.8 mg with lixisenatide 20 mcg in 404 patients inadequately controlled on metformin therapy (mean HbA_1c 8.4%), liraglutide was superior to lixisenatide in reducing HbA_1c after 26 weeks of treatment (-1.83% vs. -1.21%, p<0.0001). Significantly more patients achieved HbA_1c below 7% with liraglutide compared to lixisenatide (74.2% vs. 45.5%, p<0.0001), as well as the HbA_1c target below or equal 6.5% (54.6% vs. 26.2%, p<0.0001). Significantly greater reduction in fasting plasma glucose was achieved with liraglutide than lixisenatide (-2.85 vs. -1.70 mmol/l, p<0.0001).Body weight loss was observed in both treatment arms (-4.3 kg with liraglutide and ‑3.7 kg with lixisenatide). The safety profile of liraglutide and lixisenatide was overall comparable. Gastrointestinal adverse events were more frequently reported with liraglutide treatment (43.6% vs. 37.1%). No new safety information was identified with liraglutide.

10.       DATE OF REVISION OF THE TEXT

02/2016

Changes:

5.1      Pharmacodynamic properties

Sentence added:

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.

10.      DATE OF REVISION OF THE TEXT

09/2015

4.9      Overdose

From clinical trials and marketed use, overdoses have been reported of up to 40 times (72 mg) the recommended maintenance dose. Generally, the patients Events reported included severe nausea, and severe vomiting and diarrhoea. None of the patients reported severe included hypoglycaemia. All patients recovered without complications.

4.2      Posology and method of administration

"sulphonylurea" changed to sulfonylurea

 Patients with renal impairment

Wording changed to:

No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance 60–90 ml/min and 30–59 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 end­stage renal disease (see section 5.2).

4.4      Special warnings and precautions for use

Wording changed to:

Acute pancreatitis

Use 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

4.8      Undesirable effects

Wording changed to:

Patients >70 years may experience more gastrointestinal effects when treated with liraglutide.

Patients with mild and moderate renal impairment (creatinine clearance 60­90 ml/min and 30–59 ml/min, respectively) may experience more gastrointestinal effects when treated with liraglutide.

5.1      Pharmacodynamic properties

Sentences added:

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).

Use in patients with renal impairment

In 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 HbA_1c after 26 weeks (–1.05% vs –0.38%). Significantly more patients achieved HbA_1c 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 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.

Renal impairment:

Sentence added:

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

9.         DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Last renewal date added:

Date of last renewal: 11/04/2014

10.      DATE OF REVISION OF THE TEXT

Revision date changed to

12/2014

4.1 Therapeutic indications

Victoza is indicated for treatment of adults with type 2 diabetes mellitus to achieve glycaemic control:In combination with:

Inserted text in bold: “oral glucose-lowering medicinal products and/or basal insulin when these,together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1for available data on the different combinations)”.

Deleted:– Metformin or a sulphonylurea, in patients with insufficient glycaemic control despite maximal

tolerated dose of monotherapy with metformin or sulphonylurea.

In combination with:

– Metformin and a sulphonylurea or metformin and a thiazolidinedione in patients with

insufficient glycaemic control despite dual therapy.

4.2      Posology and method of administration

Text in bold added:

Victoza can be added to existing sulphonylurea or to a combination of metformin and sulphonylurea therapy or a basal insulin. When Victoza is added to sulphonylurea therapy or basal insulin, a reduction in the dose of sulphonylurea 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 sulphonylurea or a basal insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea or the basal insulin.

4.4      Special warnings and precautions for use

Liraglutide is not a substitute for insulin.

Text deleted:The addition of liraglutide in patients already treated with insulin has not been evaluated and is therefore not recommended.

Hypoglycaemia

Text in bold added:

Patients receiving liraglutide in combination with a sulphonylurea 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 sulphonylurea or basal insulin.

4.7      Effects on ability to drive and use machines

Text in bold added:

Victoza 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 Victoza is used in combination with a sulphonylurea or a basal insulin.

4.8      Undesirable effects

Hypoglycaemia

Text in bold added:

The risk of hypoglycaemia is low with combined use of basal insulin and liraglutide (1.0 events per subject year, see section 5.1).

5.1      Pharmacodynamic properties

Clinical study information added.

10.      DATE OF REVISION OF THE TEXT

Text in bold added:

04/2014 

In section 4.8 Allergic reactions updated

Allergic 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, oedema have been reported with marketed use of Victoza.

In section 4.9 Overdose information updated

From clinical trials and marketed use overdoses have been reported up to 40 times the recommended maintenance dose (72 mg). Events reported included severe nausea and severe vomiting. None of the reports included severe hypoglycaemia. All patients recovered without complications.

In section 10. Date of Revision of Text updated

10/2012

In Section  5.1  Pharmacodynamic properties, has been updated to include this Clinical data.

Other clinical data

In an open label study comparing the efficacy and safety of Victoza (1.2 mg and 1.8 mg) and sitagliptin (a DPP-4 inhibitor, 100 mg) in patients inadequately controlled on metformin therapy (mean HbA_1c 8.5%), Victoza at both doses was statistically superior to sitagliptin treatment in reducing HbA_1c after 26 weeks (‑1.24%, ‑1.50% vs ‑0.90%, p<0.0001). Patients treated with Victoza 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 Victoza experienced transient nausea vs subjects treated with sitagliptin (20.8% and 27.1% for liraglutide vs. 4.6% for sitagliptin). The reductions in HbA_1c and superiority vs sitagliptin observed after 26 weeks of Victoza 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 Victoza after 52 weeks of treatment resulted in additional and statistically significant reduction in HbA_1c (‑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 Section 10, Date of Revision is: 04/2012

Other clinical data

In an open label study comparing the efficacy and safety of Victoza 1.8 mg once daily and exenatide 10 mcg twice daily in patients inadequately controlled on metformin and/or sulphonylurea therapy (mean HbA_1c 8.3%), Victoza was statistically superior to exenatide treatment in reducing HbA_1c after 26 weeks (–1.12% vs –0.79%; estimated treatment difference: –0.33; 95% CI –0.47 to –0.18). Significantly more patients achieved HbA_1c below 7% with Victoza 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 Victoza after 26 weeks of treatment resulted in an additional and statistically significant reduction in HbA_1c (-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.

The change concerns an update of the product information to include the term ‘urticaria’ in section 4.8 describing spontaneous reports, reflecting postmarketing surveillance reports and a recommendation by the internal Victoza^â safety committee.

4.1 Special warnings and precautions for use

Text added:

Victoza is not a substitute for insulin.

The addition of liraglutide in patients already treated with insulin has not been evaluated and is therefore not recommended.

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

Under Insulin  text added:
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.

4.6 Word Fertility added to Pregnancy and lactation sentence.

Fertility

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

5.1 Pharmacodynamic properties

Text added:
In a 52 week clinical trial, the addition of insulin detemir to Victoza® 1.8 mg and metformin in patients not achieving glycemic targets on Victoza® and metformin alone, resulted in a HbA1c decrease from baseline of 0.54%, compared to 0.20% in the Victoza® 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 subject years). The addition of liraglutide in patients already treated with insulin has not been evaluated (see section 4.4).

10. Date of revision of text
11/2011