4.1. Therapeutic indications

Wegovy tablets are 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.

For trial results with respect to the effect on cardiovascular events, obesity-related heart failure, populations studied and background therapies see section 5.1.

4.2. Posology and method of administration

Posology

The starting dose for orally administered semaglutide is 1.5 mg once daily. After one month at this dose, the dose escalation steps for orally administered semaglutide once daily are 4 mg, 9 mg and 25 mg with a minimum duration of 1 month at each dose level. The dose should be escalated until 25 mg (maintenance dose). If needed, the dose can be maintained at the previous dose level.

The maximum recommended single daily dose of orally administered semaglutide is 25 mg. Orally administered semaglutide should always be used as only one tablet per day. Taking more than one tablet a day should not be done to achieve the effect of a higher dose.

Switching from semaglutide injection (subcutaneous (s.c)) to semaglutide tablets (oral)

The effect of switching between semaglutide tablets and semaglutide injection cannot easily be predicted because oral semaglutide displays higher pharmacokinetic variability in absorption compared to semaglutide injection.

Patients treated with semaglutide injection 2.4 mg once weekly can be transitioned to semaglutide 25 mg tablets once daily.

Patients can start semaglutide tablets one week after their last dose of semaglutide injection.

Patients with type 2 diabetes

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

When initiating semaglutide in patients with type 2 diabetes, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia, see section 4.4.

Missed dose

If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day.

Special populations

Elderly (≥ 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 or moderate 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 severe renal impairment (eGFR < 30 mL/min/1.73m2) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Patients with hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment. Experience with the use of semaglutide in patients with severe hepatic impairment is limited. Semaglutide 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 sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of orally administered semaglutide in children and adolescents below 18 years have not been established. No data is available.

Method of administration

Wegovy is a tablet for once-daily oral use.

– This medicinal product should be taken on an empty stomach after a recommended fasting period of at least 8 hours (see section 5.2).

– It should be swallowed whole with a sip of water (up to half a glass of water equivalent to 120 mL). Tablets should not be split, crushed or chewed, as it is not known whether this impacts absorption of semaglutide.

– Patients should wait at least 30 minutes before eating, drinking or taking other oral medicinal products. Waiting less than 30 minutes decreases the absorption of semaglutide (see sections 4.5 and 5.2).

– Adherence to the dosing regimen is recommended for optimal effect of semaglutide tablets.

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).

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).

Treatment response

If the treatment response with semaglutide tablets is lower than expected, the treating physician should be aware that the absorption of orally administered semaglutide may be variable; therefore, adherence to the dosing regimen is recommended for optimal effect.

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 in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy.

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

The 1.5 mg, 4 mg and 9 mg tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

The 25 mg tablets contain 23 mg sodium per tablet, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

Semaglutide delays gastric emptying which may influence the absorption of other oral medicinal products.

Effects of semaglutide on other medicinal products

Thyroxine

Total exposure (Area Under the Curve (AUC)) of thyroxine (adjusted for endogenous levels) was increased by 33% following administration of a single dose of levothyroxine. Maximum exposure (Cmax) was unchanged. Monitoring of thyroid parameters should be considered when treating patients with semaglutide at the same time as levothyroxine.

Warfarin and other coumarin derivatives

Semaglutide did not change the AUC or Cmax of R- and S-warfarin following a single dose of warfarin, 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.

Rosuvastatin

AUC of rosuvastatin was increased by 41% [90% CI: 24; 60] when co-administered with semaglutide. Based on the wide therapeutic index of rosuvastatin the magnitude of changes in the exposure is not considered clinically relevant.

Digoxin, oral contraceptives, metformin, furosemide

No clinically relevant change in AUC or Cmax of digoxin, oral contraceptives (containing ethinylestradiol and levonorgestrel), metformin or furosemide was observed when concurrently administered with semaglutide.

Interactions with medicinal products with very low bioavailability (1%) have not been evaluated.

Effects of other medicinal products on semaglutide

Omeprazole

No clinically relevant change in AUC or Cmax of semaglutide was observed when taken with omeprazole.

In a trial investigating the pharmacokinetics of semaglutide co-administered with five other tablets, the AUC of semaglutide decreased by 34% and Cmax by 32%. This suggests that the presence of multiple tablets in the stomach influences the absorption of semaglutide if co-administered at the same time. After administering semaglutide, the patients should wait 30 minutes before taking other oral medicinal products (see section 4.2).

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 (see section 4.5).

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

No measurable concentrations of semaglutide were found in breast milk of lactating women. Salcaprozate sodium was present in breast milk and some of its metabolites were excreted in breast milk at low concentrations. As a risk to a breast-fed child cannot be excluded, Wegovy 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 (STEP 1-4), 2,650 adult patients were exposed to semaglutide injection. The duration of the trials was 68 weeks. The most frequently reported adverse reactions were gastrointestinal disorders including nausea, diarrhoea, constipation and vomiting.

In a 64-week phase 3b trial (OASIS 4), 204 adult patients with obesity (BMI ≥ 30 kg/m2) or with overweight (BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity, were exposed to semaglutide tablets. The safety profile of semaglutide tablets was consistent with the safety profile of semaglutide seen in the phase 3a trials with semaglutide injection.

Tabulated list of adverse reactions

Table 1 lists adverse reactions identified in clinical trials in adults and post-marketing reports. The frequencies are based, unless otherwise specified, on a pool of the semaglutide injection phase 3a trials (STEP 1-4). The adverse reactions in OASIS 4 had similar frequencies to the semaglutide injection phase 3a trials, except for Dyspepsia which had a higher frequency category. Events not relevant for oral administration are omitted in the following overview.

Adverse reactions associated with semaglutide tablets 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 1 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

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

Dyspepsiab,e

Nauseaa,b

Abdominal painb, c

Gastritisb, c

Gastrooesophageal reflux diseaseb

Eructationb

Flatulenceb

Abdominal distensionb

Acute pancreatitisa

Delayed gastric emptying

Intestinal obstructionc,d

Hepatobiliary disorders

Cholelithiasisa

Renal and urinary disorders

Urolithiasisa

Skin and subcutaneous tissue disorders

Hair lossa

Angioedema

General disorders and administration site conditions

Fatigueb,c

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) The frequency is based on the OASIS 4 phase 3 trial with semaglutide tablets

In a cardiovascular outcomes trial (SELECT), 8,803 patients were exposed to semaglutide injection 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 semaglutide injection 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 with semaglutide injection, 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

The below adverse reactions are applicable for semaglutide tablets. Data on specific adverse reactions, unless otherwise specified, pertains to the OASIS 4 phase 3 trial.

Gastrointestinal adverse reactions

The events were most frequently reported during dose escalation. Over the 64 weeks trial period, nausea occurred in 46.6% of patients when treated with semaglutide tablets (18.6% for placebo), vomiting in 30.9% (5.9% for placebo) and diarrhoea in 17.6% (8.8% for placebo). Most events were mild to moderate in severity and of short duration. Constipation occurred in 20.1% of patients treated with semaglutide tablets (9.8% for placebo) and was mild to moderate in severity and of longer duration.

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

Patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min/1.73m2) may experience more gastrointestinal effects when treated with semaglutide.

The gastrointestinal events led to permanent treatment discontinuation in 3.4% of patients treated with semaglutide tablets.

Over 68 weeks trial period for patients treated with semaglutide injection 2.4 mg, 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

Acute pancreatitis

Acute pancreatitis was reported in 0% of patients treated with semaglutide tablets and 1.0% of patients treated with placebo. The frequency of adjudication-confirmed acute pancreatitis reported in the STEP semaglutide injection phase 3a clinical trials was 0.2% for semaglutide injection and <0.1% for placebo, respectively.

Acute gallstone disease/Cholelithiasis

Cholelithiasis was reported in 2.5% and led to cholecystitis in 0% of patients treated with semaglutide tablets. Cholelithiasis and cholecystitis were reported in 1% and 0%, respectively, of patients treated with placebo. Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients treated with semaglutide injection 2.4 mg.

Hair loss

Hair loss was reported in 6.4% of patients treated with semaglutide tablets and in 2.0% of patients treated with placebo. All events were mild or moderate and half of them recovered by end of the trial.

Hair loss was reported in 2.5% of patients treated with semaglutide injection 2.4 mg and in 1.0% of patients treated with 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

A mean increase of 2 beats per minute (bpm) from a baseline mean of 72 bpm was observed in patients treated with semaglutide tablets. The proportions of subjects with an increase in pulse from baseline ≥ 20 bpm at any timepoint during the on-treatment period were 26.5% in the semaglutide tablets group vs. 20.8% in the placebo group.

A mean increase of 3 beats per minute (bpm) from a baseline mean of 72 bpm was observed in patients treated with semaglutide injection 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 with semaglutide injection 2.4 mg at any time post-baseline was low (2.9%) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect at end-of-trial. During treatment, high semaglutide concentrations might have lowered the sensitivity of the assays, hence the risk of false negatives cannot be excluded. However, in subjects testing positive for antibodies during and after treatment, the presence of antibodies was transient and with no apparent impact on efficacy and safety.

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 injection 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 injection 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 injection and placebo groups when used in combination with sulfonylurea and/or insulin (0.065 events/patient year with semaglutide injection and 0.098 events/patient year with placebo).

Hypoglycaemia in patients without type 2 diabetes

In a cardiovascular outcomes trial for semaglutide injection (SELECT) in adult patients without type 2 diabetes, 3 episodes of serious hypoglycaemia were reported in semaglutide injection 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 semaglutide injection (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 injection 2.4 mg vs placebo, respectively) was observed in STEP 2.

Fractures

In the cardiovascular outcomes trial for semaglutide injection (SELECT) in adults, more fractures of the hip and pelvis were reported on semaglutide injection 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 for semaglutide injection (SELECT), 1.2% of semaglutide injection treated patients and 0.8% of patients receiving placebo reported urolithiasis, including serious reactions that were reported more frequently among patients receiving semaglutide injection (0.6%) than placebo (0.4%).

Bilirubin

In the cardiovascular outcomes trial for semaglutide injection 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 semaglutide injection treated patients versus 0.2% (14/8579) of placebo-treated patients.

Dysaesthesia

Events related to a clinical picture of altered skin sensation such as sensitive skin, hyperaesthesia, paraesthesia, skin burning sensation and allodynia were reported in 4.9% of patients treated with semaglutide tablets. No events were reported in patients treated with placebo. The events were mild to moderate in severity and most patients recovered while on continued 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.

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.