Saxenda 6 mg/ml) Solution for injection

Adults Saxenda u00ae is indicated as an adjunct to a reduced-calorie diet and increased physical activity for medically supervised chronic weight management programme in adult patients with an initial Body Mass Index (BMI) of:

• u2265 30 kg/m2 (obese), or
• u2265 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight related comorbidity such as dysglycaemia (pre-diabetes and type 2 diabetes mellitus), hypertension, dyslipidaemia, or obstructive sleep apnoea.

Adolescents Saxenda u00ae can be used as an adjunct to a healthy nutrition and physical activity counselling for weight management in adolescent patients from the age of 12 years and above with:

• body weight above 60 kg and
• obesity (BMI corresponding to u2265 30 kg/m2 for adults by international cut-off points) *.

*IOTF BMI cut-off points for obesity by sex between 12u201318 years Age (years) Body mass index 30 kg/m2 Males Females 12 26,02 26,67 12,5 26,43 27,24 13 26,84 27,76 13,5 27,25 28,20 14 27,63 28,57 14,5 27,98 28,87 15 28,30 29,11 15,5 28,60 29,29 16 28,88 29,43 16,5 29,14 29,56 17 29,41 29,69 17,5 29,70 29,84 18 30,00 30,00

Posology The starting dose is 0,6 mg once daily. The dose should be increased to 3,0 mg once daily in increments of 0,6 mg with at least one-week intervals to improve gastro-intestinal tolerability (see Table 1). If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Daily doses higher than 3,0 mg are not recommended.

Table 1 Dose escalation schedule

Treatment with Saxenda u00ae should be discontinued after 12 weeks on the 3,0 mg/day dose if a patient has not lost at least 5 % of the initial body weight.

Patients with type 2 diabetes mellitus Saxenda u00ae should not be used in combination with another GLP-1 receptor agonist. When initiating Saxenda u00ae, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia. Blood glucose self-monitoring may be necessary to adjust the dose of insulin or insulin-secretagogues.

Special populations Elderly patients (u2265 65 years old) No dose adjustment is required based on age. Due to limited experience in patients u2265 75 years of age, Saxenda u00ae should be used with caution in these patients. Patients with renal impairment No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance u2265 30 mL/min). There is limited experience in patients with severe renal impairment (creatinine clearance < 30 mL/min). Saxenda u00ae is currently not recommended for use in patients with severe renal impairment including patients with end-stage renal disease (see section Special population under 5.2 Pharmacokinetic properties). Patients with hepatic impairment No dose adjustment is recommended for patients with mild or moderate hepatic impairment. Saxenda u00ae is not recommended for use in patients with severe hepatic impairment and should be used cautiously in patients with mild or moderate hepatic impairment (see section Special population under 5.2 Pharmacokinetic properties). Paediatric population Saxenda u00ae is not recommended for use in children below 12 years of age or in adolescents with a body weight below or equal to 60 kg due to lack of data. For adolescents from the age of 12 to below 18 years old, similar dose escalation schedule as for adults should be applied. The dose should be increased until 3,0 mg (maintenance dose) or maximum tolerated dose has been reached. Daily doses higher than 3,0 mg are not recommended.

Method of administration Saxenda u00ae is for subcutaneous use only. It must not be administered intravenously or intramuscularly. Saxenda u00ae is administered once daily at any time, independent of meals. It should be injected in the abdomen, thigh or upper arm. Injection sites should always be rotated within the same region in order to reduce the risk of cutaneous amyloidosis (see 4.8 Undesirable effects). The injection site and timing can be changed without dose adjustment. However, it is preferable that Saxenda u00ae is injected around the same time of the day, when the most convenient time of the day has been chosen. For instructions for handling and how to administer Saxenda u00ae solution for injection in pre-filled pen refer to user instructions at the end of the professional information.

Missed dose If a dose is missed within 12 hours from when it is usually taken, the patient should take the dose as soon as possible. If there is less than 12 hours to the next dose, the patient should not take the missed dose and resume the once-daily regimen with the next scheduled dose. An extra dose or increase in dose should not be taken to make up for the missed dose.

• Hypersensitivity to liraglutide or to any of the excipients listed in section 6.1.
• Pregnancy and lactation (see 4.6 Fertility, pregnancy and lactation).

Saxenda u00ae must not be used as a substitute for insulin in patients with diabetes mellitus. There is no clinical experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and Saxenda u00ae is therefore not recommended for use in these patients. The safety and efficacy of Saxenda u00ae have not been established in patients:

• Treated with other products for weight management,
• With obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain,
• With severe renal impairment,
• With severe hepatic impairment.

Use in these patients is not recommended (see section 4.2). Cases of pulmonary aspiration have been reported in patients receiving GLP-1 RAs undergoing general anaesthesia (GA) or deep sedation despite reported adherence to preoperative fasting recommendations. Therefore, the increased risk of residual gastric content because of delayed gastric emptying should be considered prior to performing procedures with GA or deep sedation. There is limited experience in patients with inflammatory bowel disease and diabetic gastroparesis. Use of Saxenda u00ae is not recommended in these patients since it is associated with transient gastrointestinal adverse reactions, including nausea, vomiting and diarrhoea.

Pancreatitis Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Saxenda u00ae should be discontinued; if acute pancreatitis is confirmed, Saxenda u00ae should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.

Cholelithiasis and cholecystitis In clinical trials, a higher rate of cholelithiasis and cholecystitis was observed in patients treated with Saxenda u00ae than in patients on placebo. Cholelithiasis and cholecystitis may lead to hospitalisation and cholecystectomy. Patients should be informed of the characteristic symptoms of cholelithiasis and cholecystitis.

Thyroid disease In clinical trials in type 2 diabetes, thyroid adverse events, such as goitre, have been reported in particular in patients with pre-existing thyroid disease. Saxenda u00ae should therefore be used with caution in patients with thyroid disease.

Heart rate An increase in heart rate was observed in clinical trials. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should be informed of the symptoms of increased heart rate (palpitations or feelings of a racing heartbeat while at rest). For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda u00ae should be discontinued.

Dehydration Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported in patients treated with GLP-1 receptor agonists such as Saxenda u00ae. Patients treated with Saxenda u00ae should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Hypoglycaemia in overweight or obese patients with type 2 diabetes mellitus Patients with type 2 diabetes receiving Saxenda u00ae in combination with insulin and/or sulphonylurea have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of insulin and/or sulphonylurea. Blood glucose levels should be carefully monitored during treatment with Saxenda u00ae in patients with type 2 diabetes.

In vitro assessment of interaction Saxenda u00ae has shown very low potential to be involved in pharmacokinetic interactions related to cytochrome P450 (CYP) and plasma protein binding. In vivo assessment of interaction The delay of gastric emptying with Saxenda u00ae may influence absorption of concomitantly administered oral medicines. Interaction studies did not show any clinically relevant delay of absorption and therefore no dose adjustment is required.

Interaction studies have been performed with 1,8 mg liraglutide. The effect on rate of gastric emptying was equivalent between liraglutide 1,8 mg and 3 mg, (paracetamol AUC 0-300 min). Few patients treated with liraglutide reported at least one episode of severe diarrhoea. Diarrhoea may affect the absorption of concomitant oral medicines.

Warfarin and other coumarin derivatives No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Saxenda u00ae treatment in patients on warfarin or other coumarin derivatives more frequent monitoring of INR (International Normalised Ratio) is recommended.

Paracetamol (Acetaminophen) Saxenda u00ae did not change the overall exposure of paracetamol following a single dose of 1,000 mg. Paracetamol C max was decreased by 31 % and median t max was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required.

Atorvastatin Saxenda u00ae did not change the overall exposure of atorvastatin following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with Saxenda u00ae. Atorvastatin C max was decreased by 38 % and median t max was delayed from 1 h to 3 h with liraglutide.

Griseofulvin Saxenda u00ae did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin C max increased by 37 % while median t max did not change. Dose adjustments of griseofulvin and other compounds with low solubility and high permeability are not required.

Digoxin A single dose administration of digoxin 1 mg with liraglutide resulted in a reduction of digoxin AUC by 16 %; C max decreased by 31 %. Digoxin median t max was delayed from 1 h to 1,5 h. No dose adjustment of digoxin is required based on these results.

Lisinopril A single dose administration of lisinopril 20 mg with liraglutide resulted in a reduction of lisinopril AUC by 15 %; C max decreased by 27 %. Lisinopril median t max was delayed from 6 h to 8 h with liraglutide. No dose adjustment of lisinopril is required based on these results.

Oral contraceptives Liraglutide lowered ethinylestradiol and levonorgestrel C max by 12 % and 13 %, respectively, following administration of a single dose of an oral contraceptive product. t max was delayed by 1,5 h with liraglutide for both compounds. There was no clinically relevant effect on the overall exposure of either ethinylestradiol or levonorgestrel. The contraceptive effect is therefore anticipated to be unaffected when co-administered with Saxenda u00ae.

The safety of Saxenda u00ae in pregnancy and lactation has not been established. Saxenda u00ae should not be used during pregnancy and lactation (see 4.3 Contraindications). If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda u00ae should be discontinued.

Dizziness may impair the ability to drive and use machines.

Saxenda u00ae was evaluated for safety in 5 trials that enrolled 5 813 adult patients with overweight or obesity with at least one weight-related co-morbidity. Overall, gastrointestinal reactions were the most frequently reported adverse reactions during treatment with Saxenda u00ae (see section Description of selected adverse reactions below). Table 2 lists adverse reactions reported in long term phase 3 and phase 2 controlled trials in adults and post-marketing reports. Adverse reactions associated with Saxenda u00ae are listed by body system and frequency. The frequencies of the adverse reactions are based on a pool of phase 2 and 3 clinical trials. Frequency categories are defined as:

Very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 2: Adverse reactions reported in phase 2 and phase 3 controlled trials and post-marketing reports

*Hypoglycaemia (based on self-reported symptoms by patients and not confirmed by blood glucose measurements) reported in patients without type 2 diabetes mellitus treated with Saxenda u00ae in combination with diet and exercise. Please see section u2018Description of selected side effectsu2019 for further information.

** Mainly seen during the first 3 months of treatment

*** See section 4.4

u2020 ADR from post marketing sources.

a From post marketing reports

b Grouped term covering PTs intestinal obstruction, ileus, small intestinal obstruction

Description of selected adverse reactions Hypoglycaemia in patients without type 2 diabetes mellitus In clinical trials in overweight or obese patients without type 2 diabetes mellitus treated with Saxenda u00ae in combination with diet and exercise, no severe hypoglycaemic events (requiring third party assistance) were reported. Symptoms of hypoglycaemic events were reported by 1,6 % of patients treated with Saxenda u00ae and 1,1 % of patients treated with placebo, however, these events were not confirmed by blood glucose measurements. The majority of events were mild.

Hypoglycaemia in patients with type 2 diabetes mellitus In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with Saxenda u00ae in combination with diet and exercise, severe hypoglycaemia (requiring third party assistance) was reported by 0,7 % of patients treated with Saxenda u00ae and only in patients concomitantly treated with sulfonylurea. In these patients, documented symptomatic hypoglycaemia (defined as plasma glucose u2264 3,9 mmol/ L accompanied by symptoms) was reported by 43,6 % of patients treated with Saxenda u00ae and in 27,3 % of patients treated with placebo. Among patients not concomitantly treated with sulfonylurea, 15,7 % of patients treated with Saxenda u00ae and 7,6 % of patients treated with placebo reported documented symptomatic hypoglycaemic events.

Hypoglycaemia in patients with type 2 diabetes mellitus treated with insulin In a clinical trial in overweight or obese patients with type 2 diabetes mellitus treated with insulin and Saxenda u00ae in combination with diet and exercise and up to 2 OADs, severe hypoglycaemia (requiring third party assistance) was reported by 1,5 % of patients treated with Saxenda u00ae. In this trial, documented symptomatic hypoglycaemia (defined as plasma glucose u22643,9 mmol/L accompanied by symptoms) was reported by 47,2 % of patients treated with Saxenda u00ae and by 51,8 % of patients treated with placebo. Among patients concomitantly treated with sulfonylurea, 60,9% of patients treated with Saxenda u00ae and 60,0 % of patients treated with placebo reported documented symptomatic hypoglycaemic events.

Gastrointestinal adverse reactions The reactions usually occurred during the first weeks of treatment and diminished within a few days or weeks on continued treatment. Patients u2265 65 years of age may experience more gastrointestinal effects when treated with Saxenda u00ae. Patients with mild or moderate renal impairment (creatinine clearance u2265 30 mL/min) may experience more gastrointestinal effects when treated with Saxenda u00ae.

Skin and subcutaneous tissue disorders Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing cutaneous amyloidosis. There may be a potential risk of change in Saxenda u00ae absorption or effect following Saxenda u00ae injections at sites with cutaneous amyloidosis.

Allergic reactions Cases of anaphylactic reactions with symptoms such as hypotension, palpitations, dyspnoea, or oedema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life threatening.

Tachycardia In clinical trials tachycardia was reported in 0,6 % of patients treated with Saxenda u00ae and in 0,1 % of patients treated with placebo. The majority resolved during continued treatment with Saxenda u00ae.

Paediatric population In a clinical trial conducted in adolescents of 12 years to less than 18 years with obesity, 125 patients were exposed to Saxenda u00ae for 56 weeks. Overall, the frequency, type and severity of adverse reactions in the adolescents with obesity were comparable to that observed in the adult population. Vomiting occurred with a 2-fold higher frequency in adolescents compared to adults. No effects on growth or pubertal development were found.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Novo Nordisk (Pty) Ltd. at info [email protected] or telephone 010 500 8699 (toll free).

With overdose, the patients reported severe nausea, vomiting and diarrhoea, but recovered without complications. Severe hypoglycaemia has also been observed. In the event of overdosage, appropriate supportive treatment should be initiated according to the patientu2019s clinical signs and symptoms. The patient should be observed for clinical signs of dehydration and blood glucose should be monitored.