Victoza

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VICTOZA®

Composition:

Active substance: liraglutide;

1 ml of solution contains 6 mg of liraglutide – a glucagon-like peptide-1 (GLP-1) analog, produced using recombinant DNA technology in Saccharomyces cerevisiae. One pre-filled pen contains 18 mg of liraglutide in 3 ml;

Excipients: disodium dihydrogen phosphate dihydrate, propylene glycol, phenol, sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical characteristics: clear, colorless isotonic solution, pH = 8.15.

Pharmacotherapeutic group. Antidiabetic agents, glucagon-like peptide-1 (GLP-1) analogs.

ATC code A10BJ02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Liraglutide is a GLP-1 analogue with a 97% amino acid sequence homology to human GLP-1, which binds to and activates GLP-1 receptors. The GLP-1 receptor is a target for native GLP-1 (an incretin hormone endogenously secreted), which potentiates glucose-dependent insulin secretion from pancreatic β-cells. Unlike native GLP-1, the pharmacokinetic and pharmacodynamic profile of liraglutide in humans allows once-daily administration. The prolonged action of subcutaneously administered liraglutide is due to three mechanisms: self-association, which slows absorption; binding to plasma albumin; and increased resistance to degradation by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP), resulting in a prolonged elimination half-life from plasma.

The effect of liraglutide is mediated specifically through interaction with GLP-1 receptors, leading to increased levels of cyclic adenosine monophosphate (cAMP). Liraglutide stimulates glucose-dependent insulin secretion and simultaneously reduces inappropriately elevated glucagon secretion, both in a glucose-dependent manner. Thus, at high blood glucose concentrations, insulin secretion increases while glucagon secretion decreases. Conversely, during hypoglycemia, liraglutide reduces insulin secretion but does not affect glucagon secretion. The mechanism of blood glucose reduction also includes a modest delay in gastric emptying. Liraglutide reduces body weight and fat mass through mechanisms involving reduced hunger sensation and energy intake.

GLP-1 is a physiological regulator of appetite and food intake, although the exact mechanism of its action is not fully understood. In animal studies, peripheral administration of liraglutide resulted in its accumulation in specific brain regions involved in appetite regulation, where liraglutide, via specific activation of the GLP-1 receptor (GLP-1R), enhanced satiety and reduced key hunger signals, leading to body weight reduction.

GLP-1 receptors are also expressed in certain areas of the heart, blood vessels, immune system, and kidneys. In mouse models of atherosclerosis, liraglutide prevented progression of aortic plaque and reduced plaque inflammation. Furthermore, liraglutide had beneficial effects on plasma lipids. However, liraglutide did not reduce the size of pre-existing plaques.

Effects mediated by pharmacodynamics of the drug

Liraglutide exerts its effect over 24 hours and improves glycemic control by reducing fasting and postprandial blood glucose levels in patients with type 2 diabetes.

Clinical efficacy and safety

Both improved glycemic control and reduction in cardiovascular morbidity and mortality are essential components of the treatment of type 2 diabetes.

Five double-blind, randomized, controlled phase 3a clinical trials in adults (Table 1) were conducted to evaluate the effect of liraglutide on glycemic control. Treatment with liraglutide led to clinically and statistically significant improvements in glycated hemoglobin A1c (HbA1c) levels, as well as fasting and postprandial plasma glucose concentrations, compared to placebo.

These trials included 3978 patients with type 2 diabetes (2501 patients received liraglutide): 53.7% men, 46.3% women, 797 patients (508 received liraglutide) were aged ≥65 years, and 113 patients (66 received liraglutide) were aged ≥75 years.

Additional studies evaluating the effect of liraglutide were conducted in 1901 patients across four open-label, randomized, controlled clinical trials (with 464, 658, 323, and 177 patients, respectively), and one double-blind, randomized, controlled clinical trial in patients with type 2 diabetes and moderate renal impairment (279 patients).

Liraglutide was also evaluated in a large cardiovascular outcomes trial (LEADER®) involving 9340 patients with type 2 diabetes at high cardiovascular risk.

Glycemic control

Monotherapy

Monotherapy with liraglutide over 52 weeks resulted in statistically significant and sustained reductions in HbA1c levels compared to glimepiride 8 mg (–0.84% for the 1.2 mg dose, –1.14% for the 1.8 mg dose vs –0.51% with the comparator drug) in patients previously treated with diet and exercise or monotherapy with an oral antidiabetic agent at a dose not exceeding half the maximum recommended dose (Table 1).

Combination with oral antidiabetic agents

Treatment with liraglutide in combination with metformin, glimepiride, or metformin plus rosiglitazone, or with an SGLT2 inhibitor ± metformin, over 26 weeks resulted in statistically significant and sustained reductions in HbA1c levels compared to placebo (Table 1).

Table 1. Use of liraglutide in phase 3a clinical trials as monotherapy (52 weeks) and in combination with oral antidiabetic agents (26 weeks)

* Greater efficacy (p < 0.01) compared to active comparator drug.

** Greater efficacy (p < 0.0001) compared to active comparator drug.

*** Greater efficacy (p < 0.001) compared to active comparator drug.

† Non-inferior efficacy (p < 0.0001) compared to active comparator drug.

¹ All patients.

² Previous monotherapy with oral glucose-lowering agent.

³ Patients previously on diet alone.

⁴ The study with insulin glargine was open-label, and its dosing was adjusted according to insulin glargine titration guidelines.

⁵ Adding Victoza® to an SGLT2 inhibitor was studied at all registered doses of the SGLT2 inhibitor.

Insulin glargine titration recommendations:

a According to individual recommendations provided by the investigator during the screening visit, e.g., depending on whether the patient experienced hypoglycaemia.

Combination with insulin

In a 104-week clinical trial, 57 % of patients with type 2 diabetes receiving insulin degludec in combination with metformin achieved the target HbA1c level of < 7 %, while the remaining patients continued in an open-label 26-week study and were randomized to receive additional treatment with liraglutide or once-daily insulin aspart (with the largest meal). In the investigational group using insulin degludec with liraglutide, the insulin dose was reduced by 20 % to minimize the risk of hypoglycaemia. Adding liraglutide resulted in a statistically greater reduction in HbA1c levels: –0.73 % with liraglutide versus –0.40 % with the comparator, and body weight: –3.03 kg versus –0.72 kg, respectively. The frequency of hypoglycaemic events (per patient per year of treatment) was statistically significantly lower with liraglutide addition compared to adding once-daily insulin aspart (1.0 versus 8.15; rate ratio: 0.13; 95 % CI: 0.08 to 0.21).

In a 52-week clinical trial, adding insulin detemir to liraglutide in patients who did not achieve target glycaemic control with liraglutide 1.8 mg and metformin alone resulted in a reduction in HbA1c of 0.54 % from baseline compared to 0.20 % in the control group receiving liraglutide 1.8 mg and metformin. Body weight reduction was maintained. A slight increase in the number of mild hypoglycaemia events was observed (0.23 versus 0.03 events per patient-year, respectively).

In the LEADER® trial (see section "Cardiovascular effects" below), 873 patients received pre-mixed insulin (with or without oral glucose-lowering agents) at baseline and for at least the subsequent 26 weeks. The mean HbA1c at baseline was 8.7 % in both the liraglutide and placebo groups. At week 26, the estimated mean change in HbA1c was –1.4 % with liraglutide and –0.5 % with placebo, resulting in a treatment difference of –0.9 [–1.00; –0.70] 95 %. The safety profile of liraglutide in combination with pre-mixed insulin was generally comparable to that observed with placebo combined with pre-mixed insulin (see section "Adverse reactions").

Experience in patients with renal impairment

In a double-blind trial comparing the efficacy and safety of liraglutide 1.8 mg versus placebo added to insulin and/or oral glucose-lowering agents in patients with type 2 diabetes and moderate renal impairment, liraglutide demonstrated superior results compared to placebo in reducing HbA1c levels after 26 weeks of treatment (–1.05 % versus –0.38 %, respectively). Significantly more patients achieved an HbA1c level below 7 % with liraglutide compared to placebo (52.8 % versus 19.5 %). Body weight decreased in both groups: –2.4 kg with liraglutide versus –1.09 kg with placebo. The relative risk of hypoglycaemia was comparable between the two treatment groups. The safety profile of liraglutide was generally similar to that observed in other liraglutide trials.

With monotherapy using Victoza®, patients who had an HbA1c level above 9.5 % before treatment showed a mean reduction of 2.1 %, while with combination therapy, the reduction was 1.1–2.5 %.

Proportion of patients with reduced HbA1c

Monotherapy with liraglutide provided a statistically significant greater proportion of patients achieving HbA1c ≤ 6.5 % at week 52 compared to patients receiving glimepiride (37.6 % with the 1.8 mg dose and 28.0 % with the 1.2 mg dose versus 16.2 % with the comparator).

After 26 weeks of treatment with liraglutide in combination with metformin, glimepiride, metformin and rosiglitazone, or with an SGLT2 inhibitor ± metformin, a statistically significant higher percentage of patients achieved HbA1c ≤ 6.5 % compared to monotherapy with these agents.

Fasting plasma glucose

Treatment with liraglutide and its combination with one or two oral antidiabetic agents resulted in a reduction in fasting plasma glucose levels of 13–43.5 mg/dL (0.72–2.42 mmol/L). This reduction occurs within the first 2 weeks of treatment.

Postprandial plasma glucose

Liraglutide reduced plasma glucose levels after all three daily meals by 31–49 mg/dL (1.68–2.71 mmol/L).

Beta-cell function

Clinical trials with liraglutide, based on data from the homeostasis model assessment of beta-cell function and proinsulin/insulin ratios, concluded that beta-cell functional status improved. After 52 weeks of treatment with liraglutide in a group of patients with type 2 diabetes (n = 29), improvements in both first- and second-phase insulin secretion were observed.

Body weight

Treatment with liraglutide in combination with metformin, metformin and glimepiride, metformin and rosiglitazone, or an SGLT2 inhibitor, with or without metformin, resulted in a sustained reduction in body weight ranging from 0.86 to 2.62 kg compared to placebo.

Greater weight reduction was observed in patients with higher baseline body mass index (BMI).

Cardiovascular effects

A retrospective analysis of serious adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke) across all medium- and long-term phase 2 and 3 trials (duration from 26 to 100 weeks), involving 5607 patients (of whom 3651 received liraglutide), showed no increased risk of cardiovascular events [event rate 0.75 (95 % CI: 0.35; 1.63)] with liraglutide compared to all comparator agents.

The Liraglutide Effect and Action in Diabetes: Evaluation and Registry (LEADER®) trial is a multicentre, placebo-controlled, double-blind clinical trial. A total of 9340 patients were randomized to receive liraglutide (4668) or placebo (4672) as an add-on to standard care aimed at lowering HbA1c and cardiovascular risk factors. The primary outcome or vital status at the end of the study was known for 99.7 % and 99.6 % of randomized patients receiving liraglutide or placebo, respectively. The duration of follow-up was a minimum of 3.5 years and a maximum of 5 years. The trial included patients aged ≥ 65 years (n = 4329) and ≥ 75 years (n = 836), and patients with mild (n = 3907), moderate (n = 1934), or severe (n = 224) renal impairment. The mean age of patients 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 time from randomization to the first occurrence of any major adverse cardiovascular events (MACE): cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Liraglutide was superior in preventing major adverse cardiovascular events compared to placebo (Figure 1). The estimated risk was consistently below 1 for all three components of MACE.

Liraglutide also significantly reduced the risk of several other major adverse cardiovascular events (primary MACE, hospitalization for unstable angina, coronary revascularization, or hospitalization for heart failure) and other secondary endpoints (Figure 2).

Figure 1.

Kaplan-Meier plot of time to first occurrence of major adverse cardiovascular event (MACE) – FAS population

Figure 2. Forest plot of individual cardiovascular events analysis – FAS population

When liraglutide was added to standard care, a significant and sustained reduction in HbA1c levels from baseline to 36 months was observed compared to placebo (–1.16 % versus –0.77 %; estimated treatment difference –0.40 % [–0.45; –0.34]). Compared to placebo, liraglutide reduced the need for insulin treatment intensification by 48 % in patients who had not previously used insulin (HR 0.52 [0.48; 0.57]).

Blood pressure and heart rate

During phase 3a trials, liraglutide reduced systolic blood pressure by 2.3 to 6.7 mm Hg from baseline compared to active comparator, which reduced systolic blood pressure by 1.9 to 4.5 mm Hg.

In long-term clinical trials, including LEADER®, liraglutide slightly increased heart rate from baseline by 2–3 beats per minute. In the LEADER® trial, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed.

Assessment of microvascular complications

In the LEADER® trial, microvascular events included nephropathy and retinopathy. Analysis of time to first microvascular event with liraglutide versus placebo showed a hazard ratio (HR) of 0.84 [0.73, 0.97]. The HR for first occurrence of nephropathy with liraglutide versus placebo was 0.78 [0.67, 0.92], and for first occurrence of retinopathy was 1.15 [0.87, 1.52].

Immunogenicity

Due to the potential immunogenic properties of medicinal products containing proteins or peptides, patients treated with liraglutide may develop antibodies to liraglutide. These were detected on average in 8.6 % of patients. Antibody formation did not lead to reduced efficacy of liraglutide.

Paediatric population

In a double-blind trial, the efficacy and safety of Victoza® 1.8 mg versus placebo added to metformin ± insulin were compared in adolescents and children aged 10 years and older with type 2 diabetes. After 26 weeks of treatment with Victoza®, HbA1c levels were more effectively reduced (–1.06 [–1.65, –0.46]) compared to placebo. After an additional 26 weeks of open-label treatment, the difference in HbA1c levels was 1.3 %, confirming sustained glycaemic control with Victoza®.

The efficacy and safety profile of Victoza® was similar to that observed in adults treated with Victoza®. Depending on adequate glycaemic control or tolerability, 30 % of study subjects continued treatment at a dose of 0.6 mg, 17 % had their dose increased to 1.2 mg, and 53 % had their dose increased to 1.8 mg.

Other clinical data

In an open-label trial, the efficacy and safety of liraglutide (1.2 mg and 1.8 mg) versus sitagliptin (a dipeptidyl peptidase-4 inhibitor, 100 mg) were compared in patients with inadequate glycaemic control on metformin (mean HbA1c = 8.5 %). After 26 weeks of treatment, both liraglutide doses significantly reduced HbA1c levels (–1.24 % and –1.50 %) compared to sitagliptin (–0.90 %, P < 0.0001). Patients treated with liraglutide experienced greater weight reduction (–2.9 kg and –3.4 kg) compared to sitagliptin (–1.0 kg, P < 0.0001). Transient nausea was more frequently observed in patients receiving liraglutide (20.8 % and 27.1 %) compared to sitagliptin (4.6 %). The greater HbA1c reduction observed with liraglutide (1.2 mg and 1.8 mg) at 26 weeks was maintained at 52 weeks (–1.29 % and –1.51 %) compared to sitagliptin (–0.88 %, P < 0.0001). Switching patients from sitagliptin after 52 weeks to liraglutide (1.2 mg and 1.8 mg) resulted in further statistically significant HbA1c reduction at week 78 of –0.24 % and –0.45 % (95 % CI: –0.41 % to –0.07 % and –0.67 % to –0.23 %), although there was no formal control group.

In an open-label trial involving patients with inadequate glycaemic control on metformin and/or sulfonylurea (mean HbA1c = 8.3 %), the efficacy and safety of liraglutide 1.8 mg (once daily) were compared to exenatide 10 µg (twice daily). After 26 weeks, liraglutide significantly reduced HbA1c levels (–1.12 %) compared to exenatide (–0.79 %), with a calculated difference between groups of –0.33 % (95 % CI: –0.47 % to –0.18 %). A significantly higher proportion of patients achieved HbA1c < 7 % with liraglutide (54.2 %) compared to exenatide (43.4 %, P = 0.0015). Body weight decreased by approximately 3 kg with both treatments. Switching patients from exenatide after 26 weeks to liraglutide resulted in additional statistically significant HbA1c reduction at week 40 of –0.32 % (95 % CI: –0.41 % to –0.24 %), although there was no formal control group. During 26 weeks of treatment, 12 serious adverse events (5.1 %) occurred in 235 patients treated with liraglutide, and 6 serious adverse events (2.6 %) occurred in 232 patients treated with exenatide. No clear pattern of organ system involvement was observed.

In an open-label trial comparing liraglutide 1.8 mg and lixisenatide 20 µg in 404 patients with inadequate glycaemic control on metformin (mean HbA1c 8.4 %), liraglutide was more effective than lixisenatide in reducing HbA1c after 26 weeks (–1.83 % versus –1.21 %, P < 0.0001). Significantly more patients achieved HbA1c < 7 % with liraglutide compared to lixisenatide (74.2 % versus 45.5 %, P < 0.0001), as well as HbA1c ≤ 6.5 % (54.6 % versus 26.2 %, P < 0.0001). Weight reduction was observed in both groups (–4.3 kg with liraglutide and –3.7 kg with lixisenatide). Gastrointestinal adverse effects occurred more frequently in patients receiving liraglutide (43.6 % versus 37.1 %).

Pharmacokinetics

Absorption

After subcutaneous administration, liraglutide is absorbed slowly, with maximum concentration reached in 8–12 hours. After a single subcutaneous dose of 0.6 mg liraglutide, the maximum concentration was 9.4 nmol/L (mean body weight approximately 73 kg). After administration of 1.8 mg liraglutide, the mean steady-state concentration (AUCτ/24) reached approximately 34 nmol/L (mean body weight approximately 76 kg). Liraglutide exposure decreases with increasing body weight. Liraglutide exposure increases proportionally with dose. The coefficient of variation for AUC after a single dose of liraglutide in the same patient was 11 %.

The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55 %.

Distribution

The 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 %).

Metabolism

Within 24 hours after a single dose of radiolabelled [3H]-liraglutide administered to healthy volunteers, the main component in plasma was unchanged liraglutide. Two metabolites were detected in plasma in minor amounts (≤ 9 % and ≤ 5 % of total plasma radioactivity exposure). Liraglutide is metabolized via the same pathways as large proteins. No specific organ responsible for the primary elimination pathway has been identified.

Elimination

After administration of [3H]-liraglutide, unchanged liraglutide was not detected in urine or faeces. Only a small fraction of excreted radioactivity, corresponding to metabolites related to liraglutide, was found in urine (6 %) and faeces (5 %). Radioactivity in urine and faeces was mainly excreted within the first 6–8 days as three metabolites in minor amounts.

After a single subcutaneous dose of liraglutide, the mean clearance is approximately 1.2 L/h, and the elimination half-life is approximately 13 hours.

Special patient populations

Elderly patients. Based on pharmacokinetic data from healthy volunteers and pharmacokinetic analysis in patients aged 18 to 80 years, age was concluded not to have a clinically significant effect on the pharmacokinetics of liraglutide.

Gender. Based on pharmacokinetic analysis in male and female patients and a pharmacokinetic study in healthy volunteers, gender was concluded not to have a clinically significant effect on the pharmacokinetics of liraglutide.

Ethnic origin. Based on pharmacokinetic analysis in Caucasian, Mongoloid, and Negroid patients, ethnic origin was concluded not to have any clinically significant effect on the pharmacokinetics of liraglutide.

Obesity. Based on population pharmacokinetic analysis, body mass index (BMI) was concluded not to have a significant effect on liraglutide pharmacokinetic parameters.

Hepatic impairment. The pharmacokinetics of liraglutide were studied in patients with varying degrees of hepatic impairment in a single-dose study. Exposure to liraglutide was reduced by 13–23 % in patients with mild and moderate hepatic impairment compared to healthy volunteers.

In patients with severe hepatic impairment (> 9 points on the Child-Pugh classification), exposure was significantly lower (44 %).

Renal impairment. Liraglutide exposure was reduced in patients with renal impairment compared to those with normal renal function. In patients with mild impairment (creatinine clearance 50–80 mL/min), exposure was reduced by 33 %, with moderate impairment (creatinine clearance 30–50 mL/min) by 14 %, with severe impairment (creatinine clearance < 30 mL/min) by 27 %, and in patients with end-stage renal disease requiring dialysis by 26 %. Similarly, in 26-week clinical trials in patients with type 2 diabetes and renal impairment (creatinine clearance 30–59 mL/min, see section "Pharmacodynamics"), liraglutide exposure was reduced by 26 % compared to patients with type 2 diabetes and normal renal function or mild impairment.

Paediatric population. Pharmacokinetic properties were studied in clinical trials in children with type 2 diabetes aged 10 years and older. Liraglutide exposure in adolescents and children was comparable to that in adult patients.

Preclinical safety data

Preclinical data obtained from traditional safety pharmacology, repeated-dose toxicity, and genotoxicity studies revealed no special risk to humans.

Non-lethal C-cell thyroid tumours were observed in rats and mice in 2-year carcinogenicity studies. No increase in frequency or severity of adverse effects was observed in rats. Such tumours were not observed in monkeys treated for 20 months. Tumours in rodents are attributed to a non-genotoxic, species-specific GLP-1 receptor-mediated mechanism to which rodents are partially sensitive. The relevance of this mechanism in humans is considered low but cannot be entirely excluded. No other tumours were observed with Victoza® treatment.

No direct adverse effects on fertility were observed in animal studies; however, a slight increase in early embryonic mortality was noted at the highest doses. Administration of Victoza® during mid-gestation resulted in reduced maternal body weight, delayed fetal growth, and unexplained effects on rib development in rats and skeletal development in rabbits. Slowed growth in newborn rats, persisting through weaning, was observed in the high-dose group. It remains unclear whether this effect is due to reduced milk intake caused by a direct GLP-1 effect or reduced milk production in the mother due to decreased caloric intake.

Clinical characteristics.

Indications.

Victoza® is indicated for the treatment of inadequately controlled type 2 diabetes mellitus in adults, adolescents, and children aged 10 years and older as an adjunct to diet and exercise:

• as monotherapy when the use of metformin is considered inappropriate due to intolerance or contraindications;
• in combination with other antidiabetic agents.

For results of studies on use in combination with other agents, effects on glycemic control and cardiovascular outcomes, as well as studied populations, see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics".

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the excipient section.

Interaction with other medicinal products and other forms of interaction.

In vitro, liraglutide has shown very low potential to affect the pharmacokinetics of other active substances metabolized by cytochrome P450 or plasma protein binding.

Liraglutide causes a slight delay in gastric emptying, which may affect the absorption of concomitantly administered oral medications. Interaction studies have not shown any clinically significant delay in absorption; therefore, dose adjustment is not required. However, in some patients receiving Victoza®, at least one case of severe diarrhea has been reported. Diarrhea may interfere with the absorption of concomitantly administered oral medicinal products.

Warfarin and other coumarin derivatives

Drug interaction studies have not been conducted. A clinically relevant interaction with active substances having low solubility or a narrow therapeutic index, such as warfarin, cannot be excluded. When initiating liraglutide treatment in patients receiving warfarin or other coumarin derivatives, more frequent monitoring of INR (international normalized ratio) is recommended.

Paracetamol

Liraglutide did not alter the overall exposure to paracetamol following a single 1000 mg dose. The maximum concentration of paracetamol (Cmax) was reduced by 31%, and the time to reach maximum concentration (tmax) increased by 15 minutes. No dose adjustment is required when paracetamol is used concomitantly.

Atorvastatin

Liraglutide did not alter the overall exposure to atorvastatin to a clinically significant extent following a single 40 mg dose. Therefore, no dose adjustment of atorvastatin is required when used concomitantly with Victoza®. When administered concomitantly with liraglutide, Cmax of atorvastatin decreased by 38%, and tmax increased from 1 hour to 3 hours.

Griseofulvin

Liraglutide did not alter the overall exposure to griseofulvin following a single 500 mg dose. Cmax increased by 37%, while tmax remained unchanged. Dose adjustment is not required when griseofulvin or other low-solubility, highly permeable compounds are used concomitantly.

Digoxin

Following a single 1 mg dose of digoxin administered in combination with liraglutide, a 16% reduction in the area under the concentration-time curve (AUC) for digoxin was observed, and Cmax decreased by 31%. The mean tmax of digoxin increased from 1 hour to 1.5 hours. Based on these results, dose adjustment of digoxin is not required.

Lisinopril

Following a single 20 mg dose of lisinopril, a 15% reduction in the area under the concentration-time curve (AUC) for lisinopril was observed, and Cmax decreased by 27%. The mean tmax of lisinopril increased from 6 hours to 8 hours. Based on these results, dose adjustment of lisinopril is not required.

Oral contraceptives

When a single dose of oral contraceptives was administered concomitantly, liraglutide reduced Cmax of ethinylestradiol and levonorgestrel by 12% and 13%, respectively, and tmax increased by 1.5 hours. This did not affect the overall exposure to ethinylestradiol or levonorgestrel, indicating that concomitant use of liraglutide is unlikely to impact the contraceptive efficacy of ethinylestradiol and levonorgestrel.

Insulin

In patients with stable type 2 diabetes mellitus, no signs of pharmacokinetic or pharmacodynamic interaction were observed when insulin detemir (5 IU/kg) and liraglutide (1.8 mg) were administered concomitantly.

Children

Interaction studies have been conducted only in adults.

Special precautions for use

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

Liraglutide is not a substitute for insulin. Cases of diabetic ketoacidosis have been reported following rapid discontinuation or reduction of insulin dose in insulin-dependent patients (see section "Dosage and administration").

There is no therapeutic experience with liraglutide in patients with NYHA class IV heart failure; therefore, liraglutide is not recommended for use in these patients.

Experience with liraglutide in patients with inflammatory bowel disease or diabetic gastroparesis is limited. The use of liraglutide in such patients is not recommended, as it is associated with transient gastrointestinal side effects, including nausea, vomiting, and diarrhea.

Aspiration in combination with general anesthesia or deep sedation

Cases of pulmonary aspiration have been observed in patients receiving GLP-1 receptor agonists while under general anesthesia or deep sedation. Therefore, prior to any procedure involving general anesthesia or deep sedation, the increased risk of residual gastric contents due to delayed gastric emptying should be considered (see section "Side effects").

Acute pancreatitis

Acute pancreatitis has been observed during treatment with GLP-1 receptor agonists.

Patients should be informed about the typical symptoms of acute pancreatitis. If pancreatitis is suspected, liraglutide therapy should be discontinued. Reinitiation of liraglutide treatment is not recommended if acute pancreatitis is confirmed (see sections "Side effects" and "Pharmacodynamic properties").

Thyroid disorders

During clinical trials, adverse reactions related to the thyroid gland, such as goiter, were observed, particularly in patients with pre-existing thyroid disorders. Therefore, liraglutide should be used with caution in these patients.

Hypoglycemia

The risk of hypoglycemia is increased in patients receiving liraglutide in combination with sulfonylureas or insulin (see section "Side effects"). The risk of hypoglycemia may be reduced by lowering the dose of sulfonylurea or insulin.

Dehydration

Symptoms of dehydration, including renal dysfunction and acute kidney injury, have been observed in patients treated with liraglutide.

Patients receiving liraglutide should be advised about the risk of dehydration due to gastrointestinal disorders and the need to take preventive measures against dehydration.

The medicinal product Victoza® contains less than 1 mmol of sodium (23 mg) and can therefore be considered essentially "sodium-free."

Traceability

To improve the traceability of biological medicinal products, it is necessary to clearly record the name and batch number of the product used.

Use during pregnancy or breastfeeding.

Pregnancy

Adequate data on the use of liraglutide in pregnant women are lacking. Animal studies have shown reproductive toxicity (see section "Preclinical safety data"). The potential risk in humans is unknown.

Liraglutide should not be used during pregnancy; insulin is recommended instead. If a patient is planning pregnancy or becomes pregnant, treatment with Victoza® should be discontinued.

Period of breastfeeding

It is unknown whether liraglutide is excreted in human breast milk. Animal studies have shown that a small amount of liraglutide and its closely related structural metabolites are excreted in milk. Preclinical studies have demonstrated a treatment-related reduction in growth rates of newborn rat pups (see section "Preclinical safety data"). Due to insufficient experience during breastfeeding, Victoza® should not be used.

Fertility

Apart from a slight reduction in the number of viable implanted embryos, animal studies did not reveal any adverse effect of the drug on fertility.

Ability to influence reaction rate when driving or operating machinery

Victoza® has no effect or has a negligible effect on the ability to drive or operate machinery. Patients should be advised to take preventive measures to avoid hypoglycemia while driving or operating machinery, particularly when Victoza® is used concomitantly with sulfonylureas or insulin.

Administration and Dosage

Dosage

To improve gastrointestinal tolerability, the initial dose is 0.6 mg of liraglutide once daily. After at least 1 week, the dose should be increased to 1.2 mg. Some patients may benefit from increasing the dose from 1.2 mg to 1.8 mg, and based on treatment response, the dose may be increased to 1.8 mg after at least 1 week of treatment for further improvement in glycemic control. A daily dose higher than 1.8 mg is not recommended.

When Victoza® is used concomitantly with a sulfonylurea or insulin, the dose of sulfonylurea or insulin should be reduced to minimize the risk of hypoglycemia (see section "Special Warnings and Precautions for Use"). Combination therapy with sulfonylureas is applicable only for adult patients.

Self-monitoring of blood glucose is not required for dose adjustment of Victoza®. However, self-monitoring of blood glucose is necessary for adjusting the dose of sulfonylurea or insulin, particularly at the beginning of treatment with Victoza® and when reducing the insulin dose. Gradual reduction of the insulin dose is recommended.

Special Patient Groups

Elderly patients (> 65 years). Dose adjustment based on age is not required (see section "Pharmacokinetics").

Renal impairment. Dose adjustment is not required in patients with mild, moderate, or severe renal impairment. There is no experience with use in patients with end-stage renal disease; therefore, Victoza® is not recommended in such patients (see sections "Pharmacodynamics" and "Pharmacokinetics").

Hepatic impairment. Dose adjustment is not recommended in patients with mild or moderate hepatic impairment. Victoza® is not recommended for patients with severe hepatic impairment (see section "Pharmacokinetics").

Route of Administration

Victoza® must not be administered intravenously or intramuscularly.

Victoza® is administered once daily at any time, independent of meals. It may be injected subcutaneously into the abdominal wall, thigh, or upper arm. The injection site and time may be changed without dose adjustment. However, it is advisable to administer Victoza® approximately at the same time each day. Additional recommendations for administration are provided in the instructions for use of the Victoza® pen.

To reduce the risk of amyloid deposition at the injection site, the injection site should always be rotated (see section "Adverse Reactions").

Instructions for Use of the Victoza® Pen

Please read these instructions carefully before using the Victoza® pen.

The Victoza® pen contains 18 mg of liraglutide. You may select the following doses: 0.6 mg, 1.2 mg, and 1.8 mg.

The pen is intended for use with disposable NovoFine® or NovoTwist® needles up to 8 mm in length and 32G in thickness.

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Always use a new needle for each injection. This will reduce the risk of contamination, infection, leakage of liraglutide, blockage of the needle opening, and inaccurate dosing.

Caution: Do not bend or damage the needle.

To minimize the risk of accidental needle stick, never reattach the previously removed inner needle cap. | | | | Pen Care * Do not attempt to repair or disassemble the pen. * Avoid exposing the pen to dust, dirt, or any liquids. * Clean the pen with a cloth moistened with mild detergent. * Do not attempt to wash, soak, or lubricate the pen — these actions may damage the pen. | | | |

Important Information * Do not give your pen to other people. * Keep your Victoza® pen stored in a place inaccessible to others (especially children). | | | | Checking Pen Function Before using a new pen for the first time, check that medication flows through the needle. If your pen has already been used, go to section "Setting the Dose", step N. | | | |

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If you have dropped the pen onto a hard surface or suspect any malfunction, attach a new disposable needle before each injection and check the dose delivery to ensure proper function. | | | | Setting the Dose Ensure the dose selector is set to "0". | | | |

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Do not attempt to set doses other than 0.6 mg, 1.2 mg, or 1.8 mg. The numbers on the display must exactly align with the indicator to ensure correct dosing. When turning the dose selector, you will hear clicks. Do not rely on the number of clicks when setting the dose. Do not use the cartridge scale to determine the dose of liraglutide to be injected, as it is not sufficiently accurate. | | | | Administering the Injection Following your doctor's or nurse's instructions on injection technique, insert the needle into the skin. Then perform the following steps. | | | |

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Always remove the needle after each injection and store the Victoza® pen without the needle attached.

This helps prevent contamination, infection, or leakage of liraglutide.

Exercise special caution when disposing of used needles to avoid injury. | | |

Children. Dose adjustment is not required for adolescents and children aged 10 years and older. Data on use in children under 10 years of age are lacking. (See sections "Pharmacodynamics" and "Pharmacokinetics").

Overdose.

In clinical trials and post-marketing reports, cases of exceeding the recommended maintenance dose by up to 40 times (72 mg) have been reported. Reactions reported included severe nausea, vomiting, diarrhea, and severe hypoglycemia.

In case of overdose, supportive treatment should be administered based on the patient's clinical signs and symptoms. The patient's clinical condition should be closely monitored to detect dehydration promptly, and blood glucose levels should be controlled.

Adverse Reactions

In five large, long-term phase 3a clinical trials, more than 2500 adult patients received Victoza® alone or in combination with metformin, glimepiride (with or without metformin), sulfonylurea (with or without metformin), or metformin + rosiglitazone.

The most common adverse effects during clinical trials were gastrointestinal disorders, among which nausea and diarrhoea occurred very commonly, and vomiting, constipation, abdominal pain, and dyspepsia occurred commonly. Gastrointestinal disorders occurred more frequently at the beginning of treatment, but their intensity usually decreased over several days or weeks with continued therapy. Headache and nasopharyngitis were also commonly reported. Hypoglycaemia occurred commonly, and very commonly when Victoza® was used concomitantly with sulfonylurea. Severe hypoglycaemia was primarily observed during combination therapy with sulfonylurea.

Below is a list of adverse reactions recorded during long-term phase 3a clinical trials, the LEADER® study (a long-term cardiovascular trial), and based on spontaneous reports received after marketing authorization. The frequency of all adverse reactions was calculated according to their incidence in phase 3a clinical trials.

The frequency of adverse reactions was assessed using the following scale: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.

Metabolism and nutrition disorders: common – hypoglycaemia, anorexia, decreased appetite; uncommon – dehydration*.

Nervous system disorders: common – headache, dizziness; uncommon – dysgeusia.

Gastrointestinal disorders: very common – nausea, diarrhoea; common – vomiting, dyspepsia, upper abdominal pain, constipation, gastritis, flatulence, abdominal distension, gastroesophageal reflux disease, gastric discomfort, toothache; uncommon – delayed gastric emptying; rare – intestinal obstruction; very rare – pancreatitis (including necrotizing pancreatitis).

Cardiac disorders: common – increased heart rate (HR).

Immune system disorders: rare – anaphylactic reactions.

Infections and infestations: common – nasopharyngitis, bronchitis.

General disorders and administration site conditions: common – fatigue, injection site reactions; uncommon – malaise.

Renal and urinary disorders: uncommon – acute renal failure, renal impairment.

Skin and subcutaneous tissue disorders: common – rash; uncommon – urticaria, pruritus; not known – cutaneous amyloidosis.

Hepatobiliary disorders: uncommon – cholelithiasis, cholecystitis.

Investigations: common – increased lipase levels*, increased amylase levels*

*Data from phase 3b and 4 clinical trials, in which these parameters were measured.

Description of selected adverse reactions

During a clinical trial of Victoza® monotherapy, the incidence of hypoglycaemia in patients receiving Victoza® was lower than in patients receiving the active comparator (glimepiride). The most common adverse reactions were gastrointestinal disorders, infections, and infestations.

Hypoglycaemia

In most cases recorded during clinical trials, confirmed hypoglycaemia was mild. No cases of severe hypoglycaemia occurred during monotherapy with liraglutide. Severe hypoglycaemia is rare and occurs primarily during combination therapy with liraglutide and sulfonylurea (0.02 cases per 100 patient-years). Hypoglycaemia is very rare (0.001 cases per 100 patient-years) when liraglutide is used in combination with other oral antidiabetic agents (i.e., not sulfonylureas). The risk of hypoglycaemia with concomitant use of liraglutide and basal insulin is low (1.0 case per 100 patient-years; see section "Pharmacological properties").

In the LEADER® study, episodes of severe hypoglycaemia were reported less frequently with liraglutide compared to placebo (1.0 vs. 1.5 cases per 100 patient-years, estimated rate ratio 0.69 [0.51 to 0.93]) (see section "Pharmacodynamics"). In patients who had previously received mixed insulins at baseline and for at least the subsequent 26 weeks, the rate of severe hypoglycaemia was 2.2 cases per 100 patient-years in both the liraglutide and placebo groups.

Gastrointestinal disorders

During combination therapy with Victoza® and metformin, nausea occurred in at least 20.7% of patients and diarrhoea in 12.6%. During combination therapy with Victoza® and sulfonylurea, nausea occurred in at least 9.1% of patients and diarrhoea in 7.9%. Most cases were of mild to moderate severity and showed a dose-dependent pattern. In most patients who experienced nausea at the beginning of treatment, the frequency and severity decreased with continued therapy.

Gastrointestinal disorders may occur more frequently in patients aged 70 years and older receiving liraglutide.

Gastrointestinal disorders may occur more frequently in patients with mild or moderate renal impairment (creatinine clearance ≤ 60–90 ml/min and 30–59 ml/min, respectively) receiving liraglutide.

Cholelithiasis and cholecystitis

A small number of cases of cholelithiasis (0.4%) and cholecystitis (0.1%) were reported during long-term controlled phase 3a clinical trials with liraglutide. In the LEADER® study, the incidence of cholelithiasis and cholecystitis was 1.5% and 1.1% with liraglutide, and 1.1% and 0.7% with placebo, respectively (see section "Pharmacodynamics").

Discontinuation of treatment

During long-term controlled trials (26 weeks or longer), the rate of discontinuation of liraglutide due to adverse reactions was 7.8%, compared to 3.4% for the comparator drug. The most common reasons for discontinuation in patients receiving liraglutide were nausea (2.8%) and vomiting (1.5%).

Injection site reactions

During long-term controlled trials (26 weeks or longer), injection site reactions were reported in approximately 2% of patients receiving Victoza®. These reactions were generally mild.

Pancreatitis

During long-term controlled phase 3 clinical trials, several cases (< 0.2%) of acute pancreatitis were reported with Victoza® treatment. Cases of pancreatitis were also reported in spontaneous post-marketing reports. In the LEADER® study, the rate of expert-adjudicated acute pancreatitis was 0.4% with liraglutide and 0.5% with placebo, respectively (see sections "Special precautions for use" and "Pharmacodynamics").

Allergic reactions

After marketing of Victoza®, allergic reactions have been reported, including urticaria, rash, and pruritus. Several cases of anaphylactic reactions with additional symptoms such as hypotension, tachycardia, dyspnoea, and oedema have also been reported. Angioedema was observed rarely (0.05%) during long-term clinical trials with Victoza®.

Cutaneous amyloidosis

Cutaneous amyloidosis may occur at the injection site (see section "Dosage and administration").

Paediatric population

Overall, the frequency, type, and severity of adverse reactions in adolescents and children aged 10 years and older were similar to those in adults. The rate of confirmed hypoglycaemia was higher with liraglutide (0.58 cases/patient-year) compared to placebo (0.29 cases/patient-year). In patients who were receiving insulin prior to a confirmed hypoglycaemic episode, the rate was higher with liraglutide (1.82 cases/patient-year) compared to placebo (0.91 cases/patient-year). No severe episodes of hypoglycaemia were reported in the liraglutide group.

Reporting of suspected adverse reactions and lack of drug efficacy

Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 30 months.

After first use – 1 month.

Storage conditions.

Keep out of reach of children. Store in a refrigerator (2°C – 8°C), away from the freezer compartment. Do not freeze.

After first use, store at temperatures below 30°C or in a refrigerator (2°C – 8°C). Do not freeze.

To protect from light, store the pen with the cap on.

Incompatibilities.

Adding any substances to Victoza® may cause degradation of liraglutide. Without compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging. A pre-filled, multi-dose, single-use pen contains a 3 ml cartridge made of glass (type 1), sealed at one end with a bromobutyl rubber plunger and at the other end with a laminated bromobutyl/polysoprene rubber seal. The pen is made of polyolefin and polyacetal.

Each pen contains 3 ml of solution, allowing administration of 30 doses of 0.6 mg, 15 doses of 1.2 mg, or 10 doses of 1.8 mg.

Packaging contains 1 or 2 pre-filled pens.

Prescription status. Prescription only.

Manufacturer. A/S Novo Nordisk, Denmark / Novo Nordisk A/S, Denmark.

Manufacturer's address and place of business.

A/S Novo Nordisk, Novo Allé, 2880, Bagsværd, Denmark. Tel. +45 4444 8888 /
Novo Nordisk A/S, Novo Allé, 2880, Bagsværd, Denmark. Tel. +45 4444 8888.