4.1. Therapeutic indications

Weight management

Adults

Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of

• ≥30 kg/m2 (obesity), or

• ≥27 kg/m2 to <30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity.

4.2. Posology and method of administration

Posology

Adults

The maintenance dose of semaglutide 2.4 mg once-weekly is reached by starting with a dose of 0.25 mg. To reduce the likelihood of gastrointestinal symptoms, the dose should be escalated over a 16-week period to a maintenance dose of 2.4 mg once weekly (see Table 1).

If needed, for weight management in patients with obesity (see section 4.1), the dose can be increased to 7.2 mg once weekly after a minimum of 4 weeks on the 2.4 mg dose.

In case of significant gastrointestinal symptoms, consider delaying dose escalation or lowering to the previous dose until symptoms have improved.

Table 1 Dose escalation schedule

Dose escalation

Weekly dose

Week 1–4

0.25 mg

Week 5–8

0.5 mg

Week 9–12

1 mg

Week 13–16

1.7 mg

Maintenance dose (all indications)

2.4 mg

Maintenance dose (weight management in adult patients with obesity, if needed)

7.2 mg

Weight management

If patients have been unable to lose at least 5% of their initial body weight after 6 months on treatment, a decision is required on whether to continue treatment, taking into account the benefit/risk profile in the individual patient (see section 5.1).

Adolescents

For adolescents ages 12 years and above, the same dose escalation schedule as for adults should be applied (see Table 1). The dose should be increased until 2.4 mg (maintenance dose) or maximum tolerated dose has been reached. Weekly doses higher than 2.4 mg are not recommended.

Missed dose

If a dose is missed, it should be administered as soon as possible and within 5 days after the missed dose. If more than 5 days have passed, the missed dose should be skipped, and the next dose should be administered on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation should be considered.

Special populations

Patients with type 2 diabetes

Semaglutide should not be used in combination with other GLP-1 receptor agonist products.

When initiating semaglutide, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia.

Elderly patients (≥65 years old)

No dose adjustment is required based on age. Therapeutic experience in patients ≥85 years of age is limited.

Patients with renal impairment

No dose adjustment is required for patients with mild, moderate or severe renal impairment. Experience with the use of semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with end-stage renal disease (see section 5.2).

Patients with hepatic impairment

No dose adjustment is required for patients with hepatic impairment. Experience with the use of semaglutide in patients with severe hepatic impairment is limited. Caution should be exercised when treating these patients with semaglutide (see section 5.2).

Paediatric population

No dose adjustment is required for adolescents ages 12 years and above. Doses above 2.4 mg are not recommended.

The safety and efficacy of semaglutide in children below 12 years of age have not been established.

Method of administration

Wegovy is administered once weekly at any time of the day, with or without meals.

It is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed. It should not be administered intravenously or intramuscularly.

For the 7.2 mg dose, administer either 1 injection of 7.2 mg or 3 injections of 2.4 mg one after each other, depending on the device.

When administering wegovy 7.2 mg solution for injection in pre-filled pen for single use, the pen should be pressed firmly against the skin until the yellow bar has stopped moving. The injection takes about 5-10 seconds.

For 3 injections of 2.4 mg, the injections can be given in the same body area but should be at least 5 cm apart - doses from more than one pen may need to be used and the needle should be changed between each dose.

The day of weekly administration can be changed, if necessary, as long as the time between doses is at least 3 days (>72 hours). After selecting a new dosing day, once-weekly dosing should be continued.

Patients should be advised to read the instruction for use included in the package leaflet carefully before administering the medicinal product.

For further information on administration see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Gastrointestinal effects and Dehydration

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients with impaired renal function, as nausea, vomiting, and diarrhoea may cause dehydration, which in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Acute pancreatitis

Semaglutide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.

Acute pancreatitis has been reported in patients treated with GLP-1 receptor agonists. This includes post-marketing reports of necrotising pancreatitis and reports with a fatal outcome. Patients should be informed of the symptoms of acute pancreatitis, including persistent, severe abdominal pain. Patients should be advised to seek immediate medical attention if they occur. If pancreatitis is suspected, semaglutide should be discontinued. If the diagnosis of pancreatitis is confirmed, semaglutide 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.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Data from epidemiological studies may indicate an increased risk of non-arteritic anterior ischaemic optic neuropathy (NAION) during treatment with semaglutide. There is no identified time interval for when NAION may develop following treatment start. Patients reporting a sudden loss of vision (including partial loss) should be urgently referred for ophthalmological examination and treatment with semaglutide should be discontinued if NAION is confirmed (see section 4.8).

For patients with diabetes

Semaglutide must not be used as a substitute for insulin in patients with diabetes.

Hypoglycaemia

Semaglutide lowers blood glucose and can cause hypoglycaemia. Patients should be aware of the risk of hypoglycaemia and be educated on the signs and symptoms of hypoglycaemia.

In patients with diabetes, insulin and sulfonylurea are known to cause hypoglycaemia. Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with a GLP-1 receptor agonist.

Diabetic retinopathy in patients with type 2 diabetes

In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk of developing diabetic retinopathy complications has been observed. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded. Patients with diabetic retinopathy using semaglutide should be monitored closely and treated according to clinical guidelines. There is no experience with semaglutide 2.4 mg in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy.

Patients with gastroparesis

Semaglutide treated patients with gastroparesis may experience more serious or severe gastrointestinal adverse events. Semaglutide should be used with caution in these patients, and semaglutide is not recommended if gastroparesis is severe (see section 4.8).

Populations not studied

There is no experience in patients with congestive heart failure New York Heart Association (NYHA) class IV. There is limited experience in patients aged 85 years or more.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

Traceability

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

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

As with other GLP-1 receptor agonists, semaglutide may delay gastric emptying and could potentially influence the absorption of concomitantly administered oral medicinal products. No clinically relevant effect on the rate of gastric emptying was observed with semaglutide 2.4 mg. In clinical pharmacology trials assessing the effect of semaglutide 1.0 mg on the absorption of co-administered oral medications at steady state, no clinically relevant drug-drug interactions with semaglutide was observed based on the evaluated medications. Therefore, no dose adjustment is required when co-administered with semaglutide.

Coadministration with other semaglutide-containing products or with any other GLP-1 receptor agonist is not recommended.

Oral contraceptives

Semaglutide is not anticipated to decrease the effectiveness of oral contraceptives as semaglutide did not change the overall exposure of ethinylestradiol and levonorgestrel to a clinically relevant degree, when an oral contraceptive combination medicinal product (0.03 mg ethinylestradiol/0.15 mg levonorgestrel) was co-administered with semaglutide. Exposure of ethinylestradiol was not affected; an increase of 20% was observed for levonorgestrel exposure at steady state. Cmax was not affected for any of the compounds.

Atorvastatin

Semaglutide did not change the overall exposure of atorvastatin following a single dose administration of atorvastatin (40 mg). Atorvastatin Cmax was decreased by 38%. This was assessed not to be clinically relevant.

Digoxin

Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mg twice daily over 3.5 days.

Warfarin and other coumarin derivatives

Semaglutide did not change overall exposure or Cmax of R- and S-warfarin following a single dose of warfarin (25 mg), and the pharmacodynamic effects of warfarin as measured by the international normalised ratio (INR) were not affected in a clinically relevant manner. However, cases of decreased INR have been reported during concomitant use of acenocoumarol and semaglutide. Upon initiation of semaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of INR is recommended.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with semaglutide.

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, semaglutide should be discontinued. Semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long half-life (see section 5.2).

Breast-feeding

In lactating rats, semaglutide was excreted in milk. A risk to a breast-fed child cannot be excluded. Semaglutide should not be used during breast-feeding.

Fertility

The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male fertility in rats. In female rats, an increase in oestrous length and a small reduction in number of ovulations were observed at doses associated with maternal body weight loss.

4.7. Effects on ability to drive and use machines

Semaglutide has no or negligible influence on the ability to drive or use machines. However, dizziness can be experienced mainly during the dose escalation period. Driving or use of machines should be done cautiously if dizziness occurs.

Patients with type 2 diabetes

If semaglutide is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

4.8. Undesirable effects

Summary of safety profile

In four phase 3a trials, 2,650 adult patients were exposed to semaglutide 2.4 mg. The duration of the trials was 68 weeks. Similar to other GLP-1 receptor agonists, the most frequently reported adverse reactions were gastrointestinal disorders including nausea, diarrhoea, constipation and vomiting.

Tabulated list of adverse reactions

Table 2 lists adverse reactions identified in clinical trials in adults, the SELECT trial and post-marketing reports. The frequencies are based on a pool of the phase 3a trials.

Adverse reactions associated with semaglutide 2.4 mg are listed by system organ class and frequency. Frequency categories are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 2 Frequency of adverse reactions of semaglutide

MedDRA system organ class

Very common

Common

Uncommon

Rare

Very rare

Not known

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypoglycaemia in patients with type 2 diabetesa

Hypoglycaemia in patients without type 2 diabetesa

Nervous system disorders

Headacheb

Dizzinessb

Dysaesthesiaa,c, f

Dysgeusiab,c

Eye disorders

Diabetic retinopathy in patients with type 2 diabetesa

Non- arteritic anterior ischaemic optic neuropathy (NAION)

Cardiac disorders

Increased heart ratea,c

Vascular disorders

Hypotension

Orthostatic hypotension

Gastrointestinal disorders

Vomitinga,b

Diarrhoeaa,b

Constipationa,b

Nauseaa,b

Abdominal painb, c

Gastritisb, c

Gastrooesophageal reflux diseaseb

Dyspepsiab

Eructationb

Flatulenceb

Abdominal distensionb

Acute pancreatitisa

Delayed gastric emptying

Intestinal obstruction c,d,e

Hepatobiliary disorders

Cholelithiasisa

Renal and urinary disorders

Urolithiasis

Skin and subcutaneous tissue disorders

Hair lossa

Angioedema

General disorders and administration site conditions

Fatigueb,c

Injection site reactionsc

Investigations

Increased amylasec

Increased lipasec

Increased Bilirubina

Injury

Hip Fracturea

a) See description of selected adverse reactions below

b) Mainly seen in the dose-escalation period

c) Grouped preferred terms

d) From post-marketing reports

e) Grouped term covering PTs Intestinal obstruction, Ileus, small intestinal obstruction

f) Frequency is based on the 3a program. An increased frequency has been observed with the 7.2 mg dose. Please refer to dysaesthesia subheading below for more information.

In a cardiovascular outcomes trial (SELECT), 8,803 patients were exposed to Wegovy for a median of 37.3 months and 8,801 patients were exposed to placebo for a median of 38.6 months (See section 5.1). Safety data collection was limited to serious adverse events (including death), adverse events leading to discontinuation, and adverse events of special interest. Sixteen percent (16%) of Wegovy-treated patients and 8% of placebo-treated patients, respectively, discontinued study drug due to an adverse event. Additional information from this trial is included in subsequent sections below when relevant.

In the HFpEF trials, in adults with obesity related heart failure with preserved ejection fraction (HFpEF), the adverse reaction profile was similar to that seen in the weight management phase 3a trials.

Description of selected adverse reactions

Gastrointestinal adverse reactions

The events were most frequently reported during dose escalation. Over 68 weeks, nausea occurred in 43.9% of patients when treated with semaglutide 2.4 mg (16.1% for placebo), diarrhoea in 29.7% (15.9% for placebo) and vomiting in 24.5% (6.3% for placebo). Most events were mild to moderate in severity and of short duration. Constipation occurred in 24.2% of patients treated with semaglutide 2.4 mg (11.1% for placebo) and was mild to moderate in severity and of longer duration.

The gastrointestinal events led to permanent treatment discontinuation in 4.3% of patients.

In STEP UP trials gastrointestinal events were most frequently reported during dose escalation (during the initial 20 weeks of treatment). Over 72 weeks, nausea occurred in 38.9% of patients when treated with semaglutide 7.2 mg (12.6% for placebo), diarrhoea in 24.2% (11.6% for placebo) and vomiting in 22.1% (5.7% for placebo). Most events were mild to moderate in severity and of short duration. Constipation occurred in 20.4% of patients when treated with semaglutide 7.2 mg (7.6% for placebo) and was mild to moderate in severity and of longer duration. The gastrointestinal events led to permanent discontinuation in 3.2% of patients.

Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.

Acute pancreatitis

The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.2% for semaglutide 2.4 mg and <0.1% for placebo, respectively.

Acute gallstone disease/Cholelithiasis

Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients treated with semaglutide 2.4 mg.

Hair loss

Hair loss was reported in 2.5% of patients treated with semaglutide 2.4 mg and in 1.0% of patients treated with placebo. In STEP UP trials, hair loss was reported in 5.3% of patients treated with semaglutide 7.2 mg and in 1.0% of patients on placebo. The events were mainly of mild severity and most patients recovered while on continued treatment. Hair loss was reported more frequently in patients with a greater weight loss (≥20%).

Increased heart rate

In the phase 3a trials, a mean increase of 3 beats per minute (bpm) from a baseline mean of 72 bpm was observed in patients treated with semaglutide 2.4 mg. The proportions of patients with a maximum increase from baseline ≥20 bpm/min at any timepoint during the on-treatment period were 26.0% in the semaglutide 2.4 mg group vs 15.6% in the placebo group.

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with semaglutide. The proportion of patients testing positive for anti-semaglutide antibodies at any time post-baseline was 2.9 – 10.9% for semaglutide 2.4 mg and 15.3% for semaglutide 7.2 mg. No patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect.

Hypoglycaemia in patients with type 2 diabetes

In STEP 2, clinically significant hypoglycaemia was observed in 6.2% (0.1 events/patient year) of patients treated with semaglutide 2.4 mg compared with 2.5% (0.03 events/patient year) of patients treated with placebo. One episode (0.2% of subjects, 0.002 events/patient year) was reported as severe. The risk of hypoglycaemia was increased when semaglutide 2.4 mg was used with a sulfonylurea.

In STEP-HFpEF-DM, clinically significant hypoglycaemia was observed in 4.2% of subjects in both the semaglutide and placebo groups when used in combination with sulfonylurea and/or insulin (0.065 events/patient year with semaglutide and 0.098 events/patient year with placebo).

Hypoglycaemia in patients without type 2 diabetes

In a cardiovascular outcomes trial (SELECT) in adult patients without type 2 diabetes, 3 episodes of serious hypoglycaemia were reported in Wegovy-treated patients versus 1 episode in placebo. Patients with a history of bariatric surgery (a risk factor for hypoglycaemia) had more events of serious hypoglycaemia while taking Wegovy (2.3%, 2/87) than placebo (0%, 0/97).

Diabetic retinopathy in patients with type 2 diabetes

New onset or worsening of diabetic retinopathy (4.0% vs 2.7% of patients treated with semaglutide 2.4 mg vs placebo, respectively) was observed in STEP 2.

Fractures

In the cardiovascular outcomes trial (SELECT) in adults, more fractures of the hip and pelvis were reported on Wegovy than on placebo in female patients: 1.0% (24/2448) vs. 0.2% (5/2424), and in patients ages 75 years and older: 2.4% (17/703) vs. 0.6% (4/663), respectively.

Urolithiasis

In a cardiovascular outcomes trial (SELECT), 1.2% of Wegovy-treated patients and 0.8% of patients receiving placebo reported urolithiasis, including serious reactions that were reported more frequently among patients receiving Wegovy (0.6%) than placebo (0.4%).

Bilirubin

In the cardiovascular outcomes trial in adults (SELECT), increases in total bilirubin greater than or equal to 3 times the upper limit of normal were observed in 0.3% (30/8585) of Wegovy-treated patients versus 0.2% (14/8579) of placebo-treated patients.

Dysaesthesia

Events related to a clinical picture of altered skin sensation such as dysaesthesia, paraesthesia, hyperaesthesia, burning sensation, allodynia and sensitive skin were reported in 2.1% of patients treated with Wegovy injection and 1.2% of patients treated with placebo. The events were mild to moderate in severity and most patients recovered while on continued treatment.

In STEP-UP, dysaesthesia events were reported by 21.6% of patients treated with semaglutide 7.2 mg and 0.3% of patients on placebo. Most events were mild to moderate and recovered while on treatment.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Results from several large epidemiological studies suggest that exposure to semaglutide in adults with type 2 diabetes may be associated with an approximately two-fold increase in the relative risk of developing NAION, corresponding to approximately one additional case per 10 000 person-years of treatment.

Paediatric population

In a clinical trial conducted in adolescents of 12 years to below 18 years with obesity or overweight with at least one weight-related comorbidity, 133 patients were exposed to Wegovy. The trial duration was 68 weeks.

Overall, the frequency, type and severity of adverse reactions in the adolescents were comparable to that observed in the adult population. Cholelithiasis was reported in 3.8% of patients treated with Wegovy compared to 0% of patients treated with placebo.

No effects on growth or pubertal development were found after 68 weeks of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose with semaglutide may be associated with gastrointestinal disorders which could lead to dehydration. In the event of overdose, the patient should be observed for clinical signs and appropriate supportive treatment initiated.