Saxenda^® (Solution) Instructions for Use

Marketing Authorization Holder

Novo Nordisk A/S (Denmark)

Contact Information

NOVO NORDISK LLC (Russia)

ATC Code

A10BJ02 (Liraglutide)

Active Substance

Liraglutide (Rec.INN registered by WHO)

Dosage Form

Saxenda®

Solution for subcutaneous administration 6 mg/ml: cartridge in pen-injector 3 ml 3 or 5 pcs.

Dosage Form, Packaging, and Composition

Solution for subcutaneous administration clear, colorless or almost colorless.

Excipients: disodium phosphate dihydrate, propylene glycol, phenol, sodium hydroxide/hydrochloric acid (for pH adjustment), water for injections.

3 ml – glass cartridges (1) – plastic multi-dose disposable pen-injectors for multiple injections (3) – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic agent. Glucagon-like peptide receptor agonist

Pharmacotherapeutic Group

Hypoglycemic agent – glucagon-like peptide-1 (GLP-1) analog

Pharmacological Action

Pharmacodynamics

The active substance of Saxenda^® – Liraglutide – is an acylated analog of human GLP-1, produced by recombinant DNA biotechnology using a strain of Saccharomyces cerevisiae, with 97% amino acid sequence homology to endogenous human GLP-1. Liraglutide binds to and activates the GLP-1 receptor (GLP-1R). Liraglutide is resistant to metabolic degradation, its plasma half-life after subcutaneous administration is 13 hours. The pharmacokinetic profile of liraglutide, allowing for once-daily administration, is the result of self-association leading to delayed absorption; binding to plasma proteins; and resistance to dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase (NEP).

GLP-1 is a physiological regulator of appetite and food intake, and GLP-1 receptors are located in several areas of the brain involved in appetite regulation. In animal studies, peripheral administration of liraglutide resulted in uptake of the drug in specific areas of the brain, including the hypothalamus, where Liraglutide, through specific activation of GLP-1R, enhanced satiety signals and attenuated hunger signals, thereby leading to reduced body weight.

GLP-1 receptors are also present in specific areas of the heart, blood vessels, immune system, and kidneys. In experiments on atherosclerotic mice, Liraglutide prevented further progression of aortic plaques and reduced inflammation within them. In addition, Liraglutide had a beneficial effect on plasma lipids. Liraglutide did not reduce the size of existing plaques.

Liraglutide reduces body weight in humans primarily by reducing fat mass. Weight loss occurs through reduced food intake. Liraglutide does not increase 24-hour energy expenditure. Liraglutide regulates appetite by enhancing feelings of fullness and satiety, while simultaneously reducing feelings of hunger and prospective food consumption.

Liraglutide stimulates insulin secretion and reduces inappropriately high glucagon secretion in a glucose-dependent manner, and also improves pancreatic beta-cell function, leading to reduced fasting and postprandial blood glucose concentrations. The mechanism of blood glucose reduction also includes a slight delay in gastric emptying.

In long-term clinical studies involving patients with overweight and obesity, the use of Saxenda^® in combination with a low-calorie diet and increased physical activity led to significant weight loss.

Effect on appetite, calorie intake and energy expenditure, gastric emptying, and fasting and postprandial blood glucose concentrations

The pharmacodynamic effects of liraglutide were studied in a five-week pharmacological clinical trial involving 49 obese patients (BMI 30-40 kg/m²) without diabetes mellitus (DM).

Appetite, calorie intake and energy expenditure

Weight loss with Saxenda^® is considered to be related to the regulation of appetite and food intake. Appetite was assessed before and for 5 hours after a standardized breakfast; ad libitum food intake was assessed during a subsequent lunch. Compared to placebo, Saxenda^® increased feelings of satiety and fullness after meals and reduced feelings of hunger and prospective food consumption, as well as reduced ad libitum food intake. When assessed using a respiratory chamber, no therapy-related increase in 24-hour energy expenditure was observed.

Gastric emptying

The use of Saxenda^® resulted in a slight delay in gastric emptying during the first hour after a meal, resulting in a reduced rate of increase in blood glucose concentration and overall postprandial blood glucose concentration.

Fasting and postprandial glucose, insulin, and glucagon concentrations

Fasting and postprandial glucose, insulin, and glucagon concentrations were assessed before and for 5 hours after a standardized meal. Compared to placebo, Saxenda^® reduced fasting and postprandial (AUC_{0-60 min}) blood glucose concentrations during the first hour after a meal, and also reduced the 5-hour glucose AUC and incremental glucose concentration (AUC_{0-300 min}). Furthermore, compared to placebo, Saxenda^® reduced postprandial glucagon (AUC_{0-300 min}) and insulin (AUC_{0-60 min}) concentrations and the incremental insulin concentration (iAUC_{0-60 min}) after a meal.

Fasting glucose and insulin concentrations and incremental glucose and insulin concentrations were also assessed during an oral glucose tolerance test (OGTT) with 75 g of glucose before the start of therapy and after 1 year of therapy in 3731 patients with overweight and obesity, with or without prediabetes. Compared to placebo, Saxenda^® reduced fasting and incremental glucose concentrations. The effect was more pronounced in patients with prediabetes. Furthermore, compared to placebo, Saxenda^® reduced fasting insulin concentration and increased the incremental insulin concentration.

After 160 weeks of ongoing therapy with liraglutide 3.0 mg, the plasma glucose AUC decreased, while it remained unchanged with placebo. Additionally, the insulin AUC remained relatively stable over the 160-week treatment period with liraglutide 3.0 mg, while a decrease was observed with placebo. All studied therapy effects were statistically significant in favor of liraglutide 3.0 mg.

Effect on fasting glucose concentration and incremental glucose concentration in patients with type 2 diabetes mellitus (T2DM) with overweight and obesity

Compared to placebo, Saxenda^® reduced fasting blood glucose concentration and the mean incremental postprandial blood glucose concentration (at 90 minutes after a meal, mean value for 3 meals per day).

Pancreatic beta-cell function

Clinical studies lasting up to one year with Saxenda^® in patients with overweight, with or without DM, demonstrated improvement and preservation of pancreatic beta-cell function. This was shown using measurement methods such as the homeostasis model assessment of beta-cell function (HOMA-B) and the proinsulin-to-insulin ratio.

Clinical efficacy and safety

The efficacy and safety of Saxenda^® for long-term weight management in combination with a low-calorie diet and increased physical activity were studied in 4 randomized, double-blind, placebo-controlled phase 3 SCALE trials, including a total of 5358 patients.

Body weight

Compared to placebo, more pronounced weight loss was achieved with Saxenda^® in patients with obesity/overweight in all studied groups, including those with or without prediabetes, T2DM, and moderate or severe obstructive sleep apnea. Furthermore, within the study population, a greater proportion of patients achieved weight loss of ≥5% and >10% with Saxenda^® compared to placebo. Significant weight loss was also observed in a clinical trial where patients achieved a mean weight loss of 6% with a low-calorie diet for 12 weeks prior to starting treatment with Saxenda^®. In this study, more patients maintained the weight loss achieved prior to starting Saxenda^® treatment compared to placebo (81.4% and 48.9%, respectively).

Fig. 1. Change in body weight (%) over time from baseline in patients in Study No.1 (0-56 weeks).

In a 160-week clinical trial, patients receiving Saxenda^® achieved greater weight loss compared to patients receiving placebo. Weight loss occurred primarily in the first year and was maintained over 160 weeks.

In a 160-week clinical trial, the mean percentage change in body weight and the proportion of patients achieving weight loss from baseline to 160 weeks of at least 5% and more than 10% were also significant compared to placebo.

Weight loss after 12 weeks of therapy with Saxenda^®(Liraglutide 3.0 mg)

In two 56-week studies, after 12 weeks of therapy with Saxenda^® at a dose of 3.0 mg, 67.5% and 50.4% of patients achieved weight loss of at least 5%. The mean weight loss in these patients who completed the study was 11.2% from baseline. In patients who achieved weight loss of less than 5% after 12 weeks of therapy at a dose of 3.0 mg and completed the study (1 year), the mean weight loss was 3.8%.

Glycemic control

Liraglutide therapy significantly improved glycemic parameters in subpopulations with normoglycemia, prediabetes, and T2DM.

T2DM developed in 0.2% of patients receiving Saxenda^® compared to 1.1% in the placebo group. Regression of prediabetes was observed in 69.2% of patients with Saxenda^® compared to 32.7% in the placebo group. At week 160 with continued treatment, T2DM was diagnosed in 3% of patients receiving Saxenda^® and 11% of patients receiving placebo. Compared to placebo, the time to development of T2DM with liraglutide 3.0 mg was 2.7 times longer, and the relative risk (RR) of developing T2DM with liraglutide was 0.2. At week 160, in the liraglutide 3.0 mg group, 65.9% of patients with prediabetes showed regression to normoglycemia compared to 36.3% in the placebo group.

In one study, 69.2% and 56.5% of obese patients with T2DM receiving Saxenda^® achieved the target HbA_1c<7% and ≤6.5%, respectively, compared to 27.2% and 15% in patients receiving placebo.

Cardiometabolic parameters

Compared to placebo, Saxenda^® significantly improved systolic BP, waist circumference, and fasting lipid concentrations.

In a 160-week clinical trial, the mean reduction in waist circumference was 8.2 cm with Saxenda^® and 4 cm with placebo; the reduction in systolic and diastolic BP was 4.3 mmHg and 1.5 mmHg with Saxenda^® and 2.7 mmHg and 1.8 mmHg with placebo, respectively; the reduction in LDL cholesterol concentration was 3.1 mmol/l with Saxenda^® and 0.7 mmol/l with placebo; the increase in HDL cholesterol concentration was 2.3 mmol/l with Saxenda^® and 0.5 mmol/l with placebo.

Apnea-Hypopnea Index (AHI)

Compared to placebo, the use of Saxenda^® showed a significant reduction in the severity of obstructive sleep apnea, assessed by the change in AHI from baseline.

Immunogenicity

Due to the potential immunogenic properties of protein and peptide drugs, patients may develop antibodies to liraglutide after therapy with Saxenda^®. In a clinical trial, 2.5% of patients receiving Saxenda^® developed antibodies to liraglutide. Antibody formation did not lead to a reduction in the efficacy of Saxenda^®.

Assessment of cardiovascular events

Major adverse cardiovascular events (MACE) were assessed by an external independent adjudication committee and defined as non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. In 5 double-blind controlled phase 2 and 3 clinical trials with Saxenda^®, 6 MACE were noted in patients receiving Saxenda^® and 10 MACE in patients receiving placebo. The RR with 95% CI was 0.33 for Saxenda^® compared to placebo. In a phase 3 clinical trial, the mean increase in heart rate was 2.5 beats/min in patients receiving Saxenda^®. The greatest increase in heart rate was observed after 6 weeks of therapy. This increase was reversible and disappeared after discontinuation of liraglutide therapy.

A multicenter, placebo-controlled, double-blind clinical trial “Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results” (LEADER^®) was conducted.

Compared to placebo, Liraglutide 1.8 mg significantly reduced the risk of MACE (Figure 2). The RR for MACE was consistently below 1 for all three cardiovascular events.

Fig. 2. Kaplan-Meier plot – time to first MACE – Full Analysis Set (FAS).

Liraglutide 1.8 mg also significantly reduced the risk of expanded MACE (primary MACE, unstable angina leading to hospitalization, myocardial revascularization, or hospitalization for heart failure) and other secondary endpoints.

Children and adolescents

In a double-blind clinical trial comparing the efficacy and safety of Saxenda^® versus placebo regarding weight loss in adolescents aged 12 years and older with obesity, Saxenda^® was superior to placebo in reducing BMI standard deviation score (used to assess weight loss) after 56 weeks of treatment. A greater number of patients achieved ≥5% and ≥10% reduction in BMI on liraglutide therapy than patients receiving placebo, with a more significant reduction in mean BMI and body weight. During the 26-week follow-up period without the drug, weight regain occurred with Saxenda^® compared to placebo (assessed as change in BMI standard deviation score).

Based on tolerability, for the majority of patients (82.4%) the drug dose was increased and they continued to receive the 3.0 mg dose; for the remaining patients the dose was increased and they continued to receive the drug in the dose range from 2.4 mg to 0.6 mg.

Patient-reported outcome results

Saxenda^® compared to placebo improved patient-reported scores on several measures. Significant improvement was noted in the total score on the Impact of Weight on Quality of Life-Lite (IWQoL-Lite) questionnaire and on all scales of the SF-36 quality of life questionnaire, indicating a positive impact on the physical and psychological components of quality of life.

Pharmacokinetics

Absorption

Absorption of liraglutide after subcutaneous administration is slow, time to reach C_max is about 11 hours after administration. In obese patients (BMI 30-40 kg/m²) after administration of liraglutide 3.0 mg, the mean steady-state concentration of liraglutide (AUC_t/24) reaches approximately 31 nmol/l. In the dose range from 0.6 mg to 3.0 mg, liraglutide exposure increases proportionally with the dose. The absolute bioavailability of liraglutide after subcutaneous administration is approximately 55%.

Distribution

The mean apparent V_d after subcutaneous administration of liraglutide 3.0 mg is 20-25 L (in individuals with a body weight of about 100 kg). Liraglutide is extensively bound to plasma proteins (>98%).

Metabolism

Throughout 24 hours after administration of a single dose of [³H]-liraglutide to healthy volunteers, the main component in plasma was unchanged Liraglutide. Two metabolites were detected (≤9% and ≤5% of the total plasma radioactivity level).

Elimination

Liraglutide is metabolized endogenously like large proteins without the involvement of any specific organ as the main route of elimination. After administration of a dose of [³H]-liraglutide, unchanged Liraglutide was not detected in urine or feces. Only a small part of the administered radioactivity in the form of liraglutide metabolites was excreted by the kidneys or via the intestine (6% and 5%, respectively). Radioactive substances are excreted by the kidneys or via the intestine, mainly within the first 6-8 days, and represent 3 metabolites.

The mean clearance after subcutaneous administration of 3.0 mg liraglutide is approximately 0.9-1.4 L/h, T_1/2 is approximately 13 hours.

Pharmacokinetics in special patient groups

Elderly patients. Dose adjustment based on age is not required. According to the results of a population pharmacokinetic analysis in patients with overweight and obesity aged 18-82 years, age did not have a clinically significant effect on the pharmacokinetics of liraglutide after subcutaneous administration at a dose of 3.0 mg.

Gender. Based on data from a population pharmacokinetic analysis, in women the body weight-adjusted clearance of liraglutide after subcutaneous administration at a dose of 3.0 mg is 24% lower than in men. Based on exposure-response data, dose adjustment based on gender is not required.

Ethnicity. According to the results of a population pharmacokinetic analysis that included data from studies in patients with overweight and obesity of Caucasian, Black, Asian, and Latino racial groups, ethnicity did not have a clinically significant effect on the pharmacokinetics of liraglutide after subcutaneous administration at a dose of 3.0 mg.

Body weight.The exposure of liraglutide decreases with increasing baseline body weight. The use of liraglutide at a dose of 3.0 mg daily provides adequate exposure within the body weight range of 60-234 kg, according to the assessment of the response to systemic drug exposure in clinical studies. The exposure of liraglutide in patients with a body weight greater than 234 kg has not been studied.

Patients with hepatic impairment. The pharmacokinetics of liraglutide were evaluated in patients with varying degrees of liver function impairment in a single-dose study (0.75 mg). A decrease in liraglutide exposure of 13-23% was observed in patients with mild and moderate hepatic impairment and a significant decrease in liraglutide exposure (by 44%) in patients with severe hepatic impairment (>9 points on the Child-Pugh classification) compared to healthy volunteers.

Patients with renal impairment. In a single-dose study (0.75 mg), the exposure of liraglutide was lower in patients with renal impairment compared to individuals with normal renal function. Liraglutide exposure was lower by 33%, 14%, 27%, and 26%, respectively, in patients with mild (CrCl 50-80 ml/min), moderate (CrCl 30-50 ml/min), severe renal impairment (CrCl <30 ml/min), and in patients with end-stage renal disease requiring hemodialysis.

Children and adolescents. The pharmacokinetic properties of liraglutide 3.0 mg were evaluated in clinical studies in adolescents with obesity aged from 12 years to 18 years (134 patients, body weight 62-178 kg). The exposure of liraglutide in adolescents aged 12 to 18 years was comparable to that observed in adult patients with obesity.

The pharmacokinetic properties were also assessed in a clinical pharmacology study involving children with obesity aged from 7 years to 11 years (13 patients, body weight 54-87 kg). The exposure of liraglutide 3.0 mg in children aged 7 to 11 years was comparable to that observed in adult patients after adjustment for body weight.

Indications

Adults

The drug Saxenda^® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for long-term use for weight management in adult patients with a BMI

• ≥30 kg/m² (obesity) or
• ≥27 kg/m² to <30 kg/m² (overweight) in the presence of at least one weight-related comorbidity, such as prediabetes, type 2 diabetes, hypertension, dyslipidemia, or obstructive sleep apnea.

Adolescents

The drug Saxenda^® may be used as an adjunct to healthy eating and increased physical activity for weight management in adolescents aged 12 years and older with

• A body weight above 60 kg and
• Obesity (BMI corresponding to ≥30 kg/m² for adults according to international cut-off points).*

*_{The IOTF BMI cut-off for obesity by gender from age 12 to 18 years.}

Table 1. IOTF BMI cut-off for obesity by gender from age 12 to 18 years

ICD codes

Dosage Regimen

The drug Saxenda^® is intended for subcutaneous administration only. It must not be administered intravenously or intramuscularly.

Saxenda^® is administered once daily at any time, irrespective of meals. It should be injected in the abdomen, thigh, or upper arm. The injection site and time can be changed without dose adjustment. However, it is preferable to administer the injections at approximately the same time of day after choosing the most convenient time.

Doses

The initial dose is 0.6 mg/day. The dose is increased to 3.0 mg/day, adding 0.6 mg at intervals of at least one week to improve gastrointestinal tolerability (see Table 2). If a patient does not tolerate the new dose well for 2 consecutive weeks during dose escalation, discontinuation of therapy should be considered. The use of the drug at a daily dose greater than 3.0 mg is not recommended.

Table 2. Dose escalation schedule

Adults. Saxenda^® therapy should be discontinued if, after 12 weeks of using the drug at a dose of 3.0 mg/day, the weight loss is less than 5% of the initial value.

Adolescents. Saxenda^® therapy should be discontinued and re-evaluated if, after 12 weeks of using the drug at a dose of 3.0 mg/day or the maximum tolerated dose, patients have lost less than 4% of their BMI or BMI z-score.

Patients with type 2 diabetes

Saxenda^® should not be used in combination with other GLP-1 receptor agonists.

At the start of Saxenda^® therapy, it is recommended to reduce the dose of concurrently used insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycemia. Self-monitoring of blood glucose may be necessary to adjust the dose of insulin or insulin secretagogues.

Special patient groups

Dose adjustment in elderly patients (≥65 years) is not required. Experience with the drug in patients aged ≥75 years is limited; the use of the drug in these patients is not recommended.

In patients with mild or moderate renal impairment (CrCl ≥30 ml/min), dose adjustment is not required. There is limited experience with Saxenda^® in patients with severe renal impairment (CrCl <30 ml/min). The use of Saxenda^® in such patients, including patients with end-stage renal disease, is contraindicated (see sections “Pharmacokinetics” and “Contraindications”).

In patients with mild and moderate hepatic impairment, dose adjustment is not required. The use of Saxenda^® in patients with severe hepatic impairment is contraindicated. In patients with mild or moderate hepatic impairment, the drug should be used with caution (see sections “Pharmacokinetics” and “Contraindications”).

The use of Saxenda^® in children and adolescents under 12 years of age or in adolescents with a body weight ≤60 kg is contraindicated due to lack of data (see section “Pharmacodynamics”, Clinical efficacy and safety).

For adolescents aged 12 to 18 years, the same dose escalation regimen as for adults should be applied (see Table 2). The drug dose should be escalated until a value of 3.0 mg (therapeutic dose) or the maximum tolerated dose is reached. The use of the drug at a daily dose greater than 3.0 mg is not recommended.

Missed dose

If less than 12 hours have passed since the usual time of dose administration, the patient should administer the dose as soon as possible. If less than 12 hours remain until the usual time of the next dose, the patient should not administer the missed dose but should resume administration with the next scheduled dose. An additional or increased dose should not be administered to compensate for a missed dose.

Instructions for use

Saxenda^® must not be used if it looks different from a clear and colorless or almost colorless liquid.

Saxenda^® must not be used if it has been frozen.

Saxenda^® can be administered using needles up to 8 mm in length. The pen is designed for use with NovoFine^® or NovoTwise^® disposable needles. Injection needles are not included in the package.

The patient should be informed that the used needle should be discarded after each injection in accordance with local requirements, and that the Saxenda^® pen must be stored with the needle detached. This measure helps prevent needle blockages, contamination, infection, and leakage of the drug from the pen and ensures dosing accuracy.

Instructions for patients on the use of Saxenda^® solution for subcutaneous injection 6 mg/ml in a pre-filled pen

Read these instructions carefully before using the pre-filled Saxenda^® pen.

Use the pen only after you have been instructed on how to use it by a doctor or nurse.

Start by checking the label on the pen to ensure it contains Saxenda^® 6 mg/ml, and then carefully study the illustrations below, which show the various details of the pen and needle.

If you are visually impaired or have serious vision problems and cannot read the numbers on the dose counter, do not use the pen without assistance. A person with good vision who is trained in using the pre-filled Saxenda^® pen can help you.

The pre-filled pen contains 18 mg of liraglutide and allows you to select doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, and 3.0 mg. The pen is designed for use with NovoFine^® or NovoTwise^® disposable needles up to 8 mm in length. Needles are not included.

Important information: pay special attention to information marked with (!) – this is very important for the safe use of the pen.

Pre-filled Saxenda^® pen and needle (example)

1. Preparing the pen with the needle for use

• Check the name and color code on the pen label to ensure it contains Saxenda^®. This is especially important if you use different injectable drugs. Using the wrong drug can be harmful to your health.
• Remove the cap from the pen (Fig. A).

• Make sure the solution in the pen is clear and colorless (Fig. B). Look through the residual scale window. If the drug is cloudy, the pen must not be used.

• Take a new needle and remove the protective sticker (Fig. C).

• Attach the needle to the pen and turn it so that the needle is held firmly on the pen (Fig. D).

• Remove the outer needle cap, but do not discard it (Fig. E). It will be needed after the injection is completed to safely remove the needle from the pen.

• Remove and discard the inner needle cap (Fig. F). If you try to put the inner cap back on the needle, you may prick yourself. A drop of solution may appear at the needle tip. This is normal, but you should still perform a flow check if you are using a new pen for the first time. Do not attach a new needle until you are ready to make an injection.

(!) Always use a new needle for each injection. This can prevent needle blockages, contamination, infection, and the administration of an incorrect drug dose.

(!) Never use a needle if it is bent or damaged.

2. Flow check

• Before the first injection with each new pen, perform a flow check. If the pen is already in use, proceed to step 3 “Setting the dose”.
• Turn the dose selector until the dose counter is aligned with the flow check symbol (••—) (Fig. A).

• Hold the pen with the needle pointing upwards. Press and hold the dose button until the dose counter returns to “0” (Fig. B). The “0” must be aligned with the dose pointer.

A drop of solution should appear at the needle tip. A small drop may remain at the needle tip, but it will not be injected during the injection.

If a drop of solution does not appear at the needle tip, you must repeat step 2 “Flow check”, but no more than 6 times. If a drop of solution still does not appear, change the needle and repeat step 2 “Flow check” again.

If a drop of solution still does not appear, dispose of the pen and use a new one.

(!) Always before using a new pen for the first time, make sure that a drop of solution appears at the needle tip. This ensures that the drug flows. If a drop does not appear, the drug will not be administered, even if the dose counter moves. This may indicate that the needle is blocked or damaged. If you do not perform a flow check before the first injection with a new pen, you may not receive the required dose and the expected effect of Saxenda^® will not be achieved.

3. Setting the dose

• Turn the dose selector until it shows the required dose (0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg) (Fig. A).

If the dose was selected incorrectly, you can turn the dose selector forward or backward until the correct dose is set.

The maximum dose that can be set is 3.0 mg.

The dose selector allows you to change the dose. Only the dose counter and the dose pointer show the number of mg of the drug in the dose you have selected.

You can dial up to 3.0 mg of the drug per dose. If the pen contains less than 3.0 mg, the dose counter will stop before “3.0” appears in the window.

Each turn of the dose selector produces clicks; the sound of the clicks depends on the direction in which the dose selector is rotated (forward, backward, or if the dialed dose exceeds the amount of mg of drug remaining in the pen). Do not count these clicks.

(!) Always before each injection, check how many mg of the drug you have dialed using the dose counter and the dose pointer.

Do not count the pen clicks.

The residual scale shows the approximate amount of solution remaining in the pen, so it cannot be used to measure the drug dose.

Using the dose selector, you should only select doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg. The selected dose must be exactly aligned with the dose pointer – this position ensures that you receive the correct drug dose.

How much drug is left?

• The residual scale shows the approximate amount of drug remaining in the pen (Fig. A).

• To determine exactly how much drug is left, use the dose counter (Fig. B). Turn the dose selector until the dose counter stops. If it shows “3.0”, there is at least 3.0 mg of drug left in your pen. If the dose counter stopped before “3.0” appeared in the window, this means that there is insufficient drug left in the pen to administer a full 3.0 mg dose.

If you need to administer more drug than is left in the pen

Only if you have been trained by a doctor or nurse, you may split the drug dose between two pens (the one currently in use and a new one). Use a calculator to plan the doses as recommended by your doctor or nurse.

(!) Be very careful to calculate the dose correctly.

If you are unsure how to correctly split the dose using two pens, set and administer the full dose using a new pen.

4. Administering the drug

• Insert the needle under the skin using the injection technique recommended by your doctor or nurse (Fig. A).
• Make sure the dose counter is within your field of vision. Do not touch the dose counter with your fingers – this may interrupt the injection.

• Press the dose button all the way in and hold it in this position until the dose counter shows “0” (Fig. B). The “0” must be exactly aligned with the dose pointer. You may hear or feel a click.

• Keep the needle under the skin after the dose counter has returned to “0”, and slowly count to 6 (Fig. C).

If you remove the needle from under the skin too early, you may see drug leaking from the needle. In this case, an incomplete dose of the drug will be administered.

• Remove the needle from under the skin (Fig. D). If blood appears at the injection site, press lightly with a cotton swab. Do not rub the injection site.

After the injection is completed, you may see a drop of solution at the needle tip. This is normal and does not affect the dose of the drug you have administered.

(!) Always check the dose counter to know how many mg of the drug you have administered. Hold the dose button until the dose counter shows “0”.

How to detect a blocked or damaged needle?

• If “0” does not appear on the dose counter after pressing the dose button for a long time, this may indicate a blocked or damaged needle.
• In this case, you have not received the drug, even if the dose counter has moved from the initial dose you set.

What to do with a blocked needle?

Remove the needle as described in step 5 “After the injection” and repeat all steps starting from step 1 “Preparing the pen with the needle for use”. Make sure you set the dose you need.

Never touch the dose counter during drug administration. This may interrupt the injection.

5. After the injection

• Place the outer needle cap on a flat surface and insert the needle tip into the cap without touching the cap or the needle (Fig. A).

• When the needle has entered the cap, carefully place the outer cap over the needle (Fig. B).
• Unscrew the needle and discard it, observing precautions.

• After each injection, place the cap on the pen to protect the solution inside from light (Fig. C).

Always discard the needle after each injection to ensure a comfortable injection and to avoid needle blockages. If the needle is blocked, you will not be able to administer the drug to yourself.

Discard the empty pen with the needle detached, in accordance with the recommendations given by your doctor, nurse, pharmacist, or in accordance with local requirements.

(!) Never try to put the inner cap back on the needle. You may prick yourself.

(!) Always remove the needle from the pen after each injection. This can prevent needle blockages, contamination, infection, leakage of solution, and administration of an incorrect drug dose.

(!) Additional important information

• Always store the pen and needles out of the reach of others, and especially children.
• Never share your pen and its needles with other persons.
• Persons caring for the patient should handle used needles with special care to prevent needle pricks and cross-infection.

Pen care

• Do not leave the pen in a car or any other place where it may be exposed to excessively high or low temperatures.
• Do not use Saxenda^® if it has been frozen. In this case, the expected effect of the drug will not be achieved.
• Protect the pen from dust, dirt, and all types of liquids.
• Do not wash the pen, do not immerse it in liquid, and do not lubricate it. If necessary, the pen can be cleaned with a damp cloth moistened with a mild detergent.
• Do not drop or hit the pen against a hard surface. If you drop the pen or are in doubt about its serviceability, attach a new needle and check the drug flow before making an injection.
• Refilling the pen is not allowed. The empty pen must be discarded immediately.
• Do not attempt to repair the pen yourself or disassemble it.

Adverse Reactions

The safety of Saxenda^® was evaluated in 5 double-blind, placebo-controlled trials involving 5813 patients with obesity or overweight and at least one weight-related comorbidity. Overall, gastrointestinal disorders were the most frequently reported adverse effects during therapy with Saxenda^® (see “Description of selected adverse reactions”).

Table 3 lists the adverse reactions reported during long-term controlled phase 2 and 3 trials. Adverse reactions are grouped by MedDRA system organ class and frequency. Frequency definition: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (>1/10000 to <1/1000); very rare (<1/10000).

Table 3. Adverse reactions reported during controlled phase 2 and 3 trials

* Hypoglycemia (based on patient-reported symptoms and not confirmed by blood glucose measurements), reported in patients without T2DM treated with Saxenda^® in combination with diet and physical exercise. For detailed information, see “Description of selected adverse reactions”.

** Predominantly reported during the first 3 months of therapy.

*** See “Special Precautions” section.

**** According to phases 2, 3a and 3b of the controlled clinical trial.

Description of selected adverse reactions

Hypoglycemia in patients without type 2 diabetes

In clinical trials involving patients with overweight or obesity without T2DM treated with Saxenda^® in combination with diet and physical exercise, no severe hypoglycemia (requiring assistance from a third party) was reported. Symptoms of hypoglycemia were reported by 1.6% of patients receiving Saxenda^® and 1.1% of patients receiving placebo; however, these cases were not confirmed by blood glucose measurements. In most cases, mild hypoglycemia was reported.

Hypoglycemia in patients with type 2 diabetes

In clinical trials involving patients with overweight or obesity and T2DM treated with Saxenda^® in combination with diet and physical exercise, cases of severe hypoglycemia (requiring assistance from a third party) were reported in 0.7% of patients receiving Saxenda^®, and only in patients concurrently treated with a sulfonylurea. Also, in this patient group, confirmed hypoglycemia (blood glucose ≤3.9 mmol/L combined with symptoms) was reported in 43.6% of patients receiving Saxenda^® and 27.3% of patients receiving placebo. Among patients not concurrently receiving a sulfonylurea, confirmed hypoglycemia was reported in 15.7% of patients receiving Saxenda^® and in 7.6% of patients receiving placebo.

Hypoglycemia in patients with type 2 diabetes receiving insulin

In clinical trials involving patients with overweight or obesity with type 2 diabetes treated with insulin and Saxenda^® in combination with diet and physical exercise and up to two oral hypoglycemic drugs, severe hypoglycemia (requiring assistance from a third party) was reported in 1.5% of patients receiving Saxenda^® therapy. In this study, confirmed hypoglycemia (defined as plasma glucose ≤3.9 mmol/L, accompanied by symptoms) was reported in 47.2% of patients receiving Saxenda^® therapy and in 51.8% of patients receiving placebo. Confirmed hypoglycemic episodes were reported among patients concurrently receiving sulfonylureas in 60.9% of patients receiving Saxenda^® therapy and in 60.0% of patients receiving placebo.

Gastrointestinal adverse reactions

Most gastrointestinal reactions were mild or moderate in severity, transient, and in most cases did not lead to therapy discontinuation. Reactions usually occurred in the first weeks of therapy, and their manifestations gradually decreased over several days or weeks with continued therapy.

Patients aged ≥65 years may experience more pronounced manifestations of gastrointestinal adverse reactions during therapy with Saxenda^®.

Patients with mild or moderate renal impairment (CrCl ≥30 ml/min) may experience more pronounced manifestations of gastrointestinal adverse reactions during therapy with Saxenda^®.

Allergic reactions

In the post-marketing period, several cases of anaphylactic reactions with symptoms such as arterial hypotension, palpitations, dyspnea, or peripheral edema have been reported. Anaphylactic reactions can potentially be life-threatening.

Injection site reactions

Injection site reactions have been reported in patients receiving Saxenda^®. These reactions were generally mild, transient, and in most cases resolved with continued therapy.

Tachycardia

In clinical trials, tachycardia was reported in 0.6% of patients receiving Saxenda^® and 0.1% of patients receiving placebo. Most events were mild or moderate in severity. The events were isolated and in most cases resolved with continued Saxenda^® therapy.

Children and adolescents

In a clinical trial conducted with obese adolescents aged 12 to 18 years, 125 patients received Saxenda^® therapy for 56 weeks.

Overall, the incidence, type, and severity of adverse reactions in obese adolescents were comparable to those in adult patients. Vomiting occurred twice as often in adolescents compared to adult patients.

No effect on growth or pubertal development was found.

Contraindications

• Hypersensitivity to liraglutide or any of the excipients of the drug;
• Personal or family history of medullary thyroid carcinoma;
• Multiple endocrine neoplasia type 2;
• Severe depression, suicidal thoughts or behavior, including in the medical history.

Use is contraindicated in the following patient groups and for the following conditions/diseases due to lack of data on efficacy and safety

• Severe renal failure (CrCl less than 30 ml/min);
• Severe hepatic failure;
• Children under 12 years of age;
• Adolescents aged 12 to 18 years with a body weight ≤60 kg;
• In patients aged ≥75 years;
• Pregnancy;
• Breastfeeding period;
• Chronic heart failure (CHF) functional class IV (according to NYHA classification);
• Concomitant use of other drugs for weight management;
• Use in combination with other GLP-1 receptor agonists;
• Secondary obesity due to endocrine diseases or eating disorders, or due to the use of drugs that may lead to weight gain.

In patients with diabetes, Saxenda^® should not be used as a substitute for insulin.

Experience with Saxenda^® in patients with inflammatory bowel disease and diabetic gastroparesis is limited. The use of liraglutide in such patients is not recommended, as it is associated with transient gastrointestinal adverse reactions, including nausea, vomiting, and diarrhea.

With caution

Saxenda^® should be used with caution in patients with mild to moderate hepatic impairment, thyroid diseases, and a history of acute pancreatitis.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of Saxenda^® in pregnant women are limited. Reproductive toxicity has been demonstrated in animal studies. The potential risk to humans is unknown.

The use of Saxenda^® during pregnancy is contraindicated. Therapy with Saxenda^® must be discontinued when planning pregnancy or if pregnancy occurs.

Breastfeeding period

It is unknown whether liraglutide is excreted in human breast milk. Animal studies have shown that the penetration of liraglutide and structurally related metabolites into breast milk is low. Preclinical studies have demonstrated therapy-related growth retardation in newborn suckling rat pups. Due to lack of experience, Saxenda^® is contraindicated during breastfeeding.

Fertility

With the exception of a slight reduction in the number of live embryos, results from animal studies do not indicate any adverse effects on fertility.

Use in Hepatic Impairment

In patients with mild to moderate hepatic impairment, dose adjustment is not required; the drug should be used with caution. The use of Saxenda^® in patients with severe hepatic impairment is contraindicated.

Use in Renal Impairment

In patients with mild or moderate renal impairment (CrCl ≥30 ml/min), dose adjustment is not required. There is limited experience with Saxenda^® in patients with severe renal impairment (CrCl <30 ml/min). The use of Saxenda^® in such patients, including patients with end-stage renal disease, is contraindicated.

Pediatric Use

The use of Saxenda^® in children and adolescents under 12 years of age or in adolescents with a body weight ≤60 kg is contraindicated due to lack of data.

Geriatric Use

Dose adjustment in elderly patients (≥65 years) is not required. Experience with the drug in patients aged ≥75 years is limited; use of the drug in these patients is not recommended.

Special Precautions

Saxenda^® must not be used as a substitute for insulin in patients with diabetes.

Diabetic ketoacidosis has been reported in patients receiving insulin therapy after rapid discontinuation or reduction of the insulin dose (see “Dosage and Administration” section).

Pancreatitis

The use of GLP-1 receptor agonists has been associated with the development of acute pancreatitis. Patients should be informed about the characteristic symptoms of acute pancreatitis.

If pancreatitis is suspected, the use of Saxenda^® should be discontinued; if acute pancreatitis is confirmed, therapy with Saxenda^® should not be resumed.

Cholelithiasis and cholecystitis

Clinical trials noted a higher incidence of cholelithiasis and cholecystitis in patients receiving Saxenda^® compared to patients receiving placebo. This can be partly explained by the fact that significant weight loss with Saxenda^® may increase the risk of developing cholelithiasis and, consequently, cholecystitis. Cholelithiasis and cholecystitis can lead to hospitalization and cholecystectomy. Patients should be informed about the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid diseases

In clinical trials involving patients with T2DM, adverse reactions related to the thyroid gland were noted, including increased serum calcitonin levels, goiter, and thyroid neoplasms, especially in patients who already had thyroid diseases. Saxenda^® should be used with caution in patients with thyroid diseases.

In the post-marketing period, cases of medullary thyroid carcinoma have been reported in patients treated with liraglutide. The available data are insufficient to establish or exclude a causal relationship between the occurrence of medullary thyroid carcinoma and the use of liraglutide in humans. Saxenda^® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and multiple endocrine neoplasia type 2. The patient should be informed about the risk of medullary thyroid carcinoma and about the symptoms of thyroid tumors (neck mass, dysphagia, dyspnea, persistent hoarseness).

Routine monitoring of serum calcitonin or thyroid ultrasound is of uncertain value for the early detection of medullary thyroid carcinoma in patients using Saxenda^®. A significant increase in serum calcitonin may indicate the presence of medullary thyroid carcinoma; patients with medullary thyroid carcinoma usually have calcitonin levels above 50 ng/L. If an increase in serum calcitonin is detected, the patient should be further examined. Patients with thyroid nodules detected during physical examination or thyroid ultrasound should also be further evaluated.

Heart rate

Clinical trials noted an increase in heart rate (see “Pharmacological Properties” – Clinical efficacy and safety). Heart rate should be monitored at intervals appropriate for routine clinical practice. Patients should be informed about the symptoms of tachycardia (palpitations or feeling of a rapid heartbeat at rest). In patients with clinically significant persistent resting tachycardia, therapy with Saxenda^® should be discontinued.

Dehydration

Signs and symptoms of dehydration, including impaired renal function and acute renal failure, have been reported in patients receiving GLP-1 receptor agonists. Patients receiving Saxenda^®® should be informed about the potential risk of dehydration associated with gastrointestinal side effects and about the need to prevent hypovolemia.

Hypoglycemia in patients with overweight or obesity and type 2 diabetes

The risk of hypoglycemia may be higher in patients with T2DM receiving Saxenda^® in combination with a sulfonylurea. This risk can be reduced by lowering the dose of the sulfonylurea. Adding Saxenda^® to therapy in patients receiving insulin has not been evaluated.

Suicidal thoughts and behavior

During clinical trials, 6 (0.2%) of 3384 patients receiving Saxenda^® reported suicidal thoughts, and one of the patients attempted suicide. This was not noted in patients (1941 persons) receiving placebo. Patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unexpected changes in mood or behavior. In patients with suicidal thoughts or behavior, the use of Saxenda^® should be discontinued.

It is contraindicated to use the drug Saxenda^® in patients with a history of suicide attempts or active suicidal thoughts.

Breast Cancer (BC)

In clinical trials, confirmed breast cancer was reported in 14 (0.6%) of 2379 women treated with Saxenda^® compared to 3 (0.2%) of 1300 women treated with placebo, including invasive cancer (11 cases in women treated with Saxenda^® and 3 cases in women treated with placebo) and ductal carcinoma in situ (3 cases in women treated with Saxenda^® and 1 case in a woman treated with placebo). Most cancer cases were estrogen- and progesterone-dependent. It is impossible to determine whether these cases were related to the use of Saxenda^® due to their small number. Furthermore, there is insufficient data to determine whether Saxenda^® has an effect on pre-existing breast neoplasms.

Papillary Thyroid Carcinoma

In clinical trials, confirmed papillary thyroid carcinoma was reported in 7 (0.2%) of 3291 patients treated with Saxenda^® compared to none in the placebo group (1843 patients). Of all cases, 4 carcinomas were less than 1 cm in the largest diameter and 4 were diagnosed based on histology results after a medically indicated thyroidectomy.

Colorectal Neoplasms

In clinical trials, confirmed benign colorectal neoplasms (predominantly colon adenomas) were reported in 17 (0.5%) of 3291 patients treated with Saxenda^® compared to 4 (0.2%) of 1843 patients treated with placebo. Two confirmed cases of malignant colorectal carcinoma (0.1%) were registered in patients treated with Saxenda^® and none in patients treated with placebo.

Cardiac Conduction Disorders

In clinical trials, cardiac conduction disorders, such as first-degree AV block, right bundle branch block, or left bundle branch block, were reported in 11 (0.3%) of 3384 patients treated with Saxenda^®. No development of cardiac conduction disorders was reported in patients (1941 subjects) treated with placebo.

Preclinical Safety Data

Preclinical data based on pharmacological safety studies, repeated dose toxicity, and genotoxicity studies did not reveal any specific hazard for humans.

In two-year carcinogenicity studies in rats and mice, non-lethal thyroid C-cell tumors were observed. The results obtained in rodent studies are due to the particular sensitivity of rodents to the non-genotoxic specific mechanism mediated by the GLP-1 receptor. No other therapy-related neoplasms were observed.

Studies in animals did not reveal a direct adverse effect of the drug on fertility, but a slight increase in the frequency of early embryonic death was noted when the highest doses of the drug were used.

Effect on the Ability to Drive and Use Machines

The drug Saxenda^® has no or negligible influence on the ability to drive and use machines. Due to the risk of hypoglycemia when using the drug, especially when used in combination with sulfonylureas in patients with T2DM, caution should be exercised when driving and using machines.

Overdose

Symptoms based on clinical trials and post-marketing experience with liraglutide, cases of overdose have been reported with the drug at a dose of 72 mg (24 times the recommended dose for body weight correction). Patients reported severe nausea, severe vomiting, and severe hypoglycemia.

Treatment in case of overdose, supportive therapy should be initiated according to clinical signs and symptoms. The patient should be monitored for clinical signs of dehydration and blood glucose concentration should be controlled.

Drug Interactions

In vitro Drug Interaction Assessment

Liraglutide showed a very low potential for pharmacokinetic drug interactions due to metabolism in the cytochrome P450 (CYP) system, as well as plasma protein binding.

In vivo Drug Interaction Assessment

A slight delay in gastric emptying with liraglutide may affect the absorption of concomitantly administered oral drugs. Drug interaction studies did not show any clinically significant delay in the absorption of these drugs, so dose adjustment is not required.

Interaction studies were conducted using liraglutide at a dose of 1.8 mg. The effect on the rate of gastric emptying was the same with liraglutide at doses of 1.8 mg and 3.0 mg (AUC_{0-300 min} of paracetamol). Several patients treated with liraglutide experienced at least one episode of severe diarrhea. Diarrhea may affect the absorption of oral medications used concomitantly with liraglutide.

Warfarin and Other Coumarin Derivatives

Interaction studies have not been conducted. A clinically significant interaction with active substances with low solubility or a narrow therapeutic index, such as warfarin, cannot be excluded. At the start of treatment with Saxenda^®, more frequent monitoring of INR is recommended in patients receiving warfarin or other coumarin derivatives.

Paracetamol (Acetaminophen)

Liraglutide did not alter the overall exposure of paracetamol after administration of a single 1000 mg dose of paracetamol. The C_max of paracetamol was decreased by 31%, and the median T_max was increased by 15 minutes. No dose adjustment is required when used concomitantly with paracetamol.

Atorvastatin

Liraglutide did not alter the overall exposure of atorvastatin after administration of a single 40 mg dose of atorvastatin. Therefore, no dose adjustment of atorvastatin is required when used in combination with liraglutide. The C_max of atorvastatin was decreased by 38%, and the median T_max was increased from 1 hour to 3 hours when used with liraglutide.

Griseofulvin

Liraglutide did not alter the overall exposure of griseofulvin after administration of a single 500 mg dose of griseofulvin. The C_max of griseofulvin was increased by 37%, and the median T_max was unchanged. No dose adjustment is required for griseofulvin and other compounds with low solubility and high permeability.

Digoxin

Administration of a single 1 mg dose of digoxin in combination with liraglutide resulted in a 16% decrease in the AUC of digoxin and a 31% decrease in C_max. The median T_max of digoxin increased from 1 hour to 1.5 hours. Based on these results, no dose adjustment of digoxin is required.

Lisinopril

Administration of a single 20 mg dose of lisinopril in combination with liraglutide resulted in a 15% decrease in the AUC of lisinopril and a 27% decrease in C_max. When using liraglutide, the median T_max of lisinopril increased from 6 hours to 8 hours. Based on these results, no dose adjustment of lisinopril is required.

Oral Contraceptives

Liraglutide led to a decrease in the C_max of ethinyl estradiol and levonorgestrel by 12% and 13%, respectively, after administration of a single dose of an oral hormonal contraceptive drug. The T_max of both drugs increased by 1.5 hours when using liraglutide. No clinically significant effect on the systemic exposure of ethinyl estradiol or levonorgestrel was noted. Thus, no effect on contraceptive efficacy is expected when used concomitantly with liraglutide.

Incompatibility

Substances added to the drug Saxenda^® may cause degradation of liraglutide. Due to the lack of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Storage Conditions

The drug should be stored out of the reach of children at a temperature between 2°C (35.6°F) and 8°C (46.4°F) (in a refrigerator), but not near the freezer. Do not freeze.

The used pen with the drug should be stored at a temperature not exceeding 30°C (86°F) or in a refrigerator (at a temperature between 2°C (35.6°F) and 8°C (46.4°F)). Do not freeze. Use within 1 month. Close the pen with the cap to protect from light.

Shelf Life

The shelf life is 30 months. Do not use after the expiry date stated on the pen label and packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.