Saxenda, 6 mg/ml 3 ml cartridges in syringe pens 5 pcs

How to take, the dosage

Term of Use
Saxenda® is intended for subcutaneous administration only. It must not be administered intravenously or intramuscularly.
The drug Saxenda® is administered once a day at any time, regardless of meals. It should be injected into the abdomen, thigh or shoulder. The place and time of injection can be changed without dose adjustment. However, it is advisable to inject at approximately the same time of day after choosing the most convenient time.

Doses
The initial dose is 0.6 mg per day. The dose is increased to 3.0 mg per day, adding 0.6 mg at intervals of at least one week to improve gastrointestinal tolerance (see Table 2). If the new dose is poorly tolerated by the patient for 2 consecutive weeks when increasing the dose, discontinuation of therapy should be considered. Use of the drug in a daily dose greater than 3.0 mg is not recommended.

Table 2 Dose Increase Schedule

.

Adults
Therapy with Saxenda® should be discontinued if after 12 weeks of use at a dose of 3.0 mg per day the weight loss is less than 5% of the initial value.

Adolescents
Saxenda® therapy should be discontinued and reviewed if patients have lost less than 4% of their BMI or BMI z-score after 12 weeks of 3.0 mg daily or maximum tolerated dose.

Patients with type 2 diabetes
Saxenda® should not be used in combination with other GFP-1 receptor agonists.
At the beginning of therapy with Saxenda® it is recommended to reduce the dose of concomitantly used insulin or insulin secretagogues (such as sulfonylurea preparations) to reduce the risk of hypoglycemia. Self-monitoring of blood glucose concentrations may be necessary to adjust the dose of insulin or insulin secretagogues.

Special patient groups

. Elderly patients (≥65 years)

Dosage adjustment for age is not required. There is limited experience with the drug in patients aged ≥75 years, use of the drug in these patients is not recommended.

Patients with renal impairment
In patients with mild to moderate renal impairment (CK ≥ 30 ml/min) no dose adjustment is required. There is limited experience of using Saxenda® in patients with severe renal failure (CKR < 30 ml/min). Administration of Saxenda® in such patients, including patients with terminal renal failure, is contraindicated (see Pharmacokinetics and Contraindications).

Patients with hepatic failure
In patients with hepatic failure of mild to moderate severity a dose adjustment is not required. Saxenda® is contraindicated in patients with severe hepatic impairment (see Pharmacokinetics and Contraindications). In patients with mild to moderate hepatic impairment the drug should be used with caution (see Pharmacokinetics and Caution).

Children and adolescents
The use of the drug Saxenda® in children and adolescents under 12 years of age or in adolescents with body weight less than or equal to 60 kg is contraindicated due to lack of data (see Children and adolescents
. Clinical efficacy and safety.)
For adolescents aged 12 to 18 years, the same dose escalation regimen should be used as for adults (see Table 2). The drug dose should be increased until 3.0 mg (therapeutic dose) or the maximum tolerated dose is reached. Use of the drug in a daily dose greater than 3.0 mg is not recommended.

Missed dose
If less than 12 hours have elapsed after the usual time of administration of the dose, the patient should administer the dose as soon as possible. If it is less than 12 hours before the usual time for the next dose, the patient should not administer the missed dose, but should resume the drug with the next scheduled dose. No additional or increased dose should be administered to compensate for the missed dose.

The safety of Saxenda® has been evaluated in 5 double-blind, placebo-controlled studies involving 5,813 obese or overweight adult patients with at least one overweight-related comorbidity. Overall, gastrointestinal disorders were the most frequently reported adverse effects during therapy with Saxenda® (see Description of Individual Adverse Reactions).

Table 3 provides a list of adverse reactions reported in long-term controlled phase 2 and phase 3 studies in adult patients. The adverse reactions are categorized according to MedDRA organ systems and frequency. Frequency is defined as follows: very common (>1/10); common (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10 000 to <1/1000); very rare (<1/10 000).

Table 3 Adverse reactions reported in controlled phase 2 and 3 studies in adult patients

*Hypoglycemia (based on patient-reported symptoms and not confirmed by blood glucose measurements) noted in patients without DM2 who received Saxenda® in combination with diet and exercise. For more information, see Description of Individual Adverse Reactions.
** Predominantly noted during the first 3 months of therapy.
*** See Cautionary Note.
****In accordance with Phase 2, 3a, and 3b of a controlled clinical trial

.Description of individual adverse reactions

Hypoglycemia in patients without type 2 diabetes No severe hypoglycemia (requiring third-party assistance) was observed in a CI involving overweight or obese patients without DM2 who received Saxenda® therapy in combination with diet and exercise. Symptoms of hypoglycemia were reported in 1.6% of patients receiving Saxenda® and 1.1% of patients receiving placebo; however, these cases were not confirmed by blood glucose measurements. Mild hypoglycemia was noted in most cases.

Hypoglycemia in patients with type 2 diabetes
. In a study of overweight or obese patients with T2DM treated with Saxenda® in combination with diet and exercise, cases of severe hypoglycemia (requiring third-party assistance) were observed in 0.7% of patients treated with Saxenda® and only in patients receiving concomitant therapy with sulfonylurea derivatives. Also in this group of patients, confirmed hypoglycemia (glucose concentration ≤ 3.9 mmol/L in combination with symptoms) was observed in 43.6% of patients receiving Saxenda® and 27.3% of patients receiving placebo. Among patients who did not simultaneously receive sulfonylurea, confirmed hypoglycemia was noted 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 a CI involving overweight or obese patients with type 2 diabetes who received insulin and Saxenda® therapy in combination with diet and exercise and up to two oral hypoglycemic agents, severe hypoglycemia (requiring third-party care) was noted in 1.5% of patients who received Saxenda® therapy. In this study, confirmed hypoglycemia (defined as plasma glucose levels ≤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 in 60.9% of patients receiving Saxenda® therapy and 60.0% of patients receiving placebo among patients receiving sulfonylurea derivatives simultaneously.

Adverse gastrointestinal reactions
Most gastrointestinal reactions were mild to moderate in severity, transient and, in most cases, did not lead to discontinuation of therapy. Reactions usually occurred during the first weeks of therapy, and their manifestations gradually decreased over several days or weeks with continuation of therapy.
In patients aged ≥65 years, more pronounced manifestations of adverse gastrointestinal reactions may be observed during therapy with Saxenda®.
In patients with renal insufficiency of mild or moderate degree of severity (CK ≥ 30 ml/min), more pronounced manifestations of adverse reactions from the gastrointestinal tract during Saxenda® therapy may be observed.

Allergic reactions
Several cases of anaphylactic reactions with symptoms such as arterial hypotension, palpitations, shortness of breath or peripheral edema have been reported in the post-registration period. 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 disappeared with continued therapy.

Tachycardia
In the CIs, tachycardia was reported in 0.6% of patients receiving Saxenda® and 0.1% of patients receiving placebo. Most events were mild to moderate in severity. The events were isolated and in most cases resolved with continuation of therapy with Saxenda®.

Children and adolescents
In a CI conducted with adolescents with obesity aged 12 to 18 years, 125 patients received therapy with Saxenda® 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.

Interaction

In vitro Drug Interaction Evaluation
Liraglutide has shown very low drug pharmacokinetic interactions due to metabolism in the cytochrome P-450 (CYP) system as well as binding to plasma proteins.

In vivo Drug Interaction Assessment
A slight delay in gastric emptying during liraglutide administration may affect the absorption of concomitantly administered oral drugs. Drug interaction studies have not shown any clinically significant delay in absorption of these drugs, so no dose adjustment is required.

Interaction studies were conducted with liraglutide at a dose of 1.8 mg. The effect on gastric emptying rate was similar with liraglutide at 1.8 mg and 3.0 mg doses (AUC0-300 min paracetamol). Several patients treated with liraglutide had at least one episode of severe diarrhea. Diarrhea may affect the absorption of oral medications used concomitantly with liraglutide.

Varfarin and other coumarin derivatives
No interaction studies have been conducted. Clinically significant interaction with active agents with low solubility or narrow therapeutic index, such as warfarin, cannot be excluded. At the start of treatment with Saxenda® in patients receiving warfarin or other coumarin derivatives, more frequent monitoring of the international normalized ratio (INR) is recommended.

Paracetamol (acetaminophen)
Liraglutide did not alter total paracetamol exposure after a single dose of paracetamol 1000 mg. The maximum concentration (Cmax) of paracetamol was reduced by 31% and the median tmax was increased by 15 min. No dose adjustment was required for concomitant use of paracetamol.

Atorvastatin
Liraglutide did not alter total atorvastatin exposure after a single dose of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when used in combination with liraglutide. The Cmax of atorvastatin was decreased by 38% and the median tmax was increased from 1 h to 3 h with liraglutide.

Grizeofulvin
Liraglutide did not alter total exposure to griseofulvin after a single dose of griseofulvin 500 mg. The Cmax of griseofulvin was increased by 37% and the median tmax was unchanged. No dose adjustment is required for griseofulvin and other compounds with low solubility and high permeability.

Digoxin
Administration of a single dose of 1 mg digoxin in combination with liraglutide resulted in a 16% reduction in the area under the concentration-time curve (AUC) of digoxin and a 31% reduction in Cmax. Median tmax of digoxin increased from 1 h to 1.5 h. Given these results, no dose adjustment of digoxin is required.

Lisinopril
Administration of a single dose of lisinopril 20 mg in combination with liraglutide resulted in a 15% decrease in AUC of lisinopril, a 27% decrease in Cmax. When liraglutide was used, the median tmax of lisinopril increased from 6 h to 8 h. Given these results, no dose adjustment of lisinopril is required.

Internal contraceptives
Liraglutide resulted in a 12% and 13% reduction in Cmax of ethinylestradiol and levonorgestrel, respectively, after a single dose of the oral hormonal contraceptive medication. The tmax of both drugs on liraglutide increased by 1.5 h. No clinically significant effect on systemic exposure to ethinylestradiol or levonorgestrel was observed. Thus, no effect on the contraceptive effect is expected when combined with liraglutide.

Incompatibilities
Medicinal agents added to Saxenda® may cause degradation of liraglutide. Due to the lack of compatibility studies, this drug should not be mixed with other drugs.

Special Instructions

In patients with DM, Saxenda® should not be used as an insulin substitute. Diabetic ketoacidosis has been reported in patients treated with insulin after rapid discontinuation or reduction of the insulin dose (see Dosage and administration).

Pancreatitis
Use of GFP-1 receptor agonists has been associated with the development of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, the use of Saxenda® should be discontinued; in case of confirmation of acute pancreatitis, therapy with Saxenda® should not be resumed.

Chololytiasis and cholecystitis
A higher incidence of chololytiasis and cholecystitis was noted in the CI in patients who received Saxenda® compared to patients who received placebo. This may be explained in part by the fact that a significant decrease in body weight while using Saxenda® may increase the risk of cholelithiasis and, therefore, cholecystitis. Cholecystiasis and cholecystitis may lead to hospitalization and cholecystectomy. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid disease
Adverse thyroid reactions, including increased serum calcitonin concentrations, goiter, and thyroid neoplasia, have been noted in QIs involving patients with T2DM, particularly in patients who already have thyroid disease. Saxenda® should be used with caution in patients with thyroid disease.
In the post-marketing period, cases of medullary thyroid cancer have been reported in patients receiving liraglutide. There is insufficient data to establish or exclude a causal relationship between the occurrence of medullary thyroid cancer and the use of liraglutide in humans. Saxenda® is contraindicated in patients with a history of medullary thyroid cancer, including familial, and multiple endocrine neoplasia type 2. Patients should be informed of the risk of medullary thyroid cancer and the symptoms of thyroid tumor (thickening in the neck area, dysphagia, shortness of breath, persistent hoarseness of the voice).
Routine monitoring of serum calcitonin concentration or ultrasound examination (USG) of the thyroid is not essential for the early detection of medullary thyroid cancer in patients using Saxenda®. A significant increase in serum calcitonin concentration may indicate the presence of medullary thyroid cancer, patients with medullary thyroid cancer usually have a calcitonin concentration greater than 50 ng/L. If an elevated serum calcitonin concentration is detected, further evaluation of the patient is necessary. Patients with thyroid nodules detected by physical examination or thyroid ultrasound should also be further evaluated.

Heart rate
An increase in HR has been noted in the CI (see Clinical Efficacy and Safety). HR should be monitored at intervals consistent with normal clinical practice. Patients should be informed of symptoms of tachycardia (palpitations or palpitations at rest). In patients with clinically significant persistent tachycardia at rest, therapy with Saxenda® should be discontinued.

Dehydration
Signs and symptoms of dehydration, including renal impairment and acute renal failure, have been reported in patients receiving GFP-1 receptor agonists. Patients receiving Saxenda® should be informed about the potential risk of dehydration associated with gastrointestinal side effects and the need for prevention of hypovolemia.

Hypoglycemia in overweight or obese patients with type 2 diabetes
The risk of hypoglycemia may be higher in patients with T2DM receiving Saxenda® in combination with insulin and/or sulfonylurea derivatives. This risk may be reduced by reducing the dose of insulin and/or sulfonylurea derivatives.

Suicidal thoughts and behavior
During the CI, 6 (0.2%) of 3,384 patients receiving Saxenda® reported suicidal thoughts and one patient attempted suicide. This was not noted in patients (1,941) receiving placebo. Patients should be monitored for the appearance or worsening of depression, suicidal thoughts or behavior, and/or any sudden changes in mood or behavior. In patients with suicidal thoughts or behaviors, the use of Saxenda® should be discontinued.
Saxenda® is contraindicated in patients with a history of suicide attempts or active suicidal thoughts.

Breast Cancer (BC)
. The CI reported confirmed breast cancer in 14 (0.6%) of 2,379 women receiving Saxenda® compared to 3 (0.2%) of 1,300 women receiving placebo, including invasive cancer (11 cases in women receiving Saxenda® and 3 cases in women receiving placebo) and intraductal carcinoma in situ (3 cases in women receiving Saxenda® and 1 case in women receiving placebo). Most of the cancers were estrogen- and progesterone-dependent. It is not possible to determine whether these cases were related to the use of Saxenda® because their number is too small. In addition, there is insufficient data to determine whether Saxenda® has an effect on existing breast neoplasms.

Papillary thyroid cancer
The CI reported confirmed papillary thyroid carcinoma in 7 (0.2%) of 3,291 patients treated with Saxenda® compared to no cases in the group of patients treated with placebo (1,843 patients). Of all cases, 4 carcinomas were less than 1 cm in the largest diameter, and 4 were diagnosed by histology after a medically indicated thyroidectomy.

Neoplasia of the colon and rectum
. The CI reported confirmed benign neoplasia of the colon and rectum (predominantly adenomas of the colon) in 17 (0.5%) of 3291 patients treated with Saxenda® compared to 4 (0.2%) of 1843 patients treated with placebo. There were two confirmed cases of malignant carcinoma of the colon and rectum (0.1%) in patients receiving Saxenda® and none in patients receiving placebo.

Cardiac conduction disorders
In the CI, 11 (0.3%) of 3,384 patients receiving Saxenda® reported the development of cardiac conduction disorders, such as grade 1 atrioventricular block, right bundle branch block or left bundle branch block. No development of cardiac conduction abnormalities was reported in patients (1941) receiving placebo.

Fertility
Except for a slight decrease in the number of live embryos, animal studies indicate no adverse effect on fertility.

Doclinical safety data
Preclinical data based on studies of pharmacological safety, repeated-dose toxicity, and genotoxicity have not shown any risk to humans.
Two-year carcinogenicity studies in rats and mice showed nonfatal thyroid C-cell tumors. The results obtained in rodent studies are due to the fact that rodents exhibit a particular sensitivity to the GFP receptor 1 mediated non-genotoxic specific mechanism. No other neoplasms associated with the therapy have been observed.
In animal studies, no direct adverse effect of the drug on fertility was found, but a slight increase in the incidence of early fetal death was noted with the highest doses of the drug.

Influence on ability to drive vehicles and mechanisms
The drug Saxenda® has no or negligible effect on the ability to drive vehicles and mechanisms. Due to the risk of hypoglycemia when using the drug, especially when combined with sulfonylureas in patients with DM2, caution should be exercised when driving vehicles and mechanisms.

Contraindications

– Hypersensitivity to liraglutide or any of the drug excipients;
– history of medullary thyroid cancer, including familial;
– multiple endocrine neoplasia type 2;
– severe depression, suicidal thoughts or behavior, including a history.

The use is contraindicated in the following groups of patients and in the following conditions/diseases due to lack of efficacy and safety data:

– severe renal insufficiency (creatinine clearance (CK) less than 30 ml/min);
– severe hepatic insufficiency;
– children under 12 years of age;
– adolescents within 12-18 years of age with body weight less than or equal to 60 kg
– patients aged ≥75 years;
– pregnancy and breastfeeding;
– Chronic heart failure (CHF) of functional class IV (in accordance with the NYHA classification (New York Heart Association);
– concurrent use of other drugs for body weight correction;
– use in combination with other GFP-1 receptor agonists;
– secondary obesity against the background of endocrinological diseases or eating disorders, or against the background of medications that may lead to weight gain.

In patients with diabetes Saxenda® should not be used as an insulin substitute.
The experience of using Saxenda® in patients with inflammatory bowel disease and diabetic paresis of the stomach is limited. The use of liraglutide in such patients is not recommended because it is associated with transient adverse gastrointestinal (GI) reactions, including nausea, vomiting and diarrhea.

Cautions
The drug Saxenda® is recommended with caution in patients with hepatic impairment of mild to moderate severity, thyroid disease and the presence of acute pancreatitis in the history.

Side effects

The Saxenda® clinical trial program consists of 5 completed clinical studies involving 5,813 obese or overweight patients with at least one overweight-related comorbidity. In general, gastrointestinal disorders were the most frequently reported adverse effects during therapy with Saxenda® (see section “Description of Individual Adverse Reactions”).

Description of individual adverse reactions:

Hypoglycemia in patients without type 2 diabetes

. No severe hypoglycemia (requiring third-party assistance) has been reported in clinical studies involving overweight or obese patients without type 2 diabetes mellitus treated with Saxenda® in combination with diet and exercise. Symptoms of hypoglycemia were reported in 1.6% of patients receiving Saxenda® and 1.1% of patients receiving placebo; however, these cases were not confirmed by blood glucose measurements. Mild hypoglycemia was noted in most cases.

Hypoglycemia in patients with type 2 diabetes

. In a clinical trial involving overweight or obese patients with type 2 diabetes who received Saxenda® therapy in combination with diet and exercise, cases of severe hypoglycemia (requiring third-party care) were noted in 0.7% of patients who received Saxenda® and only in patients who received sulfonylurea derivatives therapy simultaneously.

Also in this group of patients, confirmed hypoglycemia (glucose concentration ≤ 3.9 mmol/L combined with symptoms) was noted in 43.6% of patients receiving Saxenda® and 27.3% of patients receiving placebo. Among patients who did not simultaneously receive sulfonylurea, confirmed hypoglycemia was noted in 15.7% of patients receiving Saxenda® and in 7.6% of patients receiving placebo.

Adverse gastrointestinal reactions

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

In patients aged ≥ 65 years there may be more pronounced manifestations of adverse reactions from the gastrointestinal tract during therapy with Saxenda®.

In patients with renal dysfunction of mild to moderate severity (creatinine clearance ≥ 30 ml/min), more pronounced manifestations of adverse reactions from the gastrointestinal tract may be observed during Saxenda® therapy.

Allergic reactions

Several cases of anaphylactic reactions with symptoms such as arterial hypotension, palpitations, shortness of breath or peripheral edema have been reported. Anaphylactic reactions can potentially be life-threatening.

Injection site reactions

In patients receiving Saxenda®, injection site reactions have been described. These reactions were generally mild, transient and in most cases disappeared with continued therapy.

Tachycardia

In clinical studies, tachycardia was noted in 0.6% of patients receiving Saxenda® and 0.1% of patients receiving placebo. Most events were mild to moderate in severity. The events were isolated and in most cases resolved with continuation of therapy with Saxenda®.

Overdose

According to the data of clinical trials and post-registration use of liraglutide, there were cases of overdose when using the drug in doses up to 72 mg (24 times the recommended dose for body weight correction).
Patients reported severe nausea, severe vomiting and severe hypoglycemia.
In case of overdose, appropriate supportive therapy should be initiated according to clinical signs and symptoms.
The patient should be monitored for clinical signs of dehydration and blood glucose concentrations should be monitored.

Pregnancy use

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. If pregnancy is planned or occurs, therapy with Saxenda® should be discontinued.

Breastfeeding
It is unknown whether liraglutide penetrates into human breast milk. The penetration of liraglutide and structurally similar metabolites into breast milk has been demonstrated to be low in animal studies. Preclinical studies demonstrated therapy-related growth retardation in breastfed newborn rats. Due to the lack of experience, Saxenda® is contraindicated during breastfeeding.