Rybelsus · 4.4 Special warnings and precautions for use · 2

HOS-098939 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile In 10 phase 3a trials, 5 707 patients were exposed to semaglutide alone or in combination with other glucose-lowering medicinal products. The duration of the treatment ranged from 26 weeks to 7 78 weeks. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common). Tabulated list of adverse reactions Table 1 lists adverse reactions identified in phase 3 trials (further described in section 5.1) and post- marketing reports in patients with type 2 diabetes mellitus. The frequencies of the adverse reactions (except diabetic retinopathy complications and dysaesthesia, see footnotes in Table 1) are based on a pool of the phase 3a trials excluding the cardiovascular outcomes trial. The reactions are listed below by system organ class and absolute frequency. Frequencies 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) and very rare: (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Frequency of adverse reactions of oral semaglutide MedDRA Very Common Uncommon Rare Very Not system organ common Rare known class Immune Hypersensitiv Anaphylac system ityc tic disorders reaction Metabolism Hypoglycae Hypoglycae and mia when mia when nutrition used with used with disorders insulin or other oral sulfonylurea antidiabetic a productsa Decreased appetite Nervous Dizziness Dysgeusia system Dysaesthesia e disorders Headache Eye Diabetic Non- disorders retinopathy arteritic

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HOS-098945 · has-adverse-reaction-information · PDF-Seite 31

Summary of the safety profile In 10 phase 3a trials, 5 707 patients were exposed to semaglutide alone or in combination with other glucose-lowering medicinal products. The duration of the treatment ranged from 26 weeks to 31 78 weeks. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common). Tabulated list of adverse reactions Table 1 lists adverse reactions identified in phase 3 trials (further described in section 5.1) and post- marketing reports in patients with type 2 diabetes mellitus. The frequencies of the adverse reactions (except diabetic retinopathy complications and dysaesthesia, see footnotes in Table 1) are based on a pool of the phase 3a trials excluding the cardiovascular outcomes trial. The reactions are listed below by system organ class and absolute frequency. Frequencies 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) and very rare: (< 1/10 000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1 Frequency of adverse reactions of oral semaglutide MedDRA Very Common Uncommon Rare Very Not system organ common Rare known class Immune Hypersensitiv Anaphylac system ityc tic disorders reaction Metabolism Hypoglycae Hypoglycae and mia when mia when nutrition used with used with disorders insulin or other oral sulfonylurea antidiabetic a productsa Decreased appetite Nervous Dizziness Dysgeusia system Dysaesthesia e disorders Headache Eye Diabetic Non- disorders retinopathy arteritic

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HOS-098941 · has-contraindication-information · PDF-Seite 28

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 28

HOS-098935 · has-contraindication-information · PDF-Seite 4

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

HOS-098940 · has-indication-information · PDF-Seite 27

Rybelsus is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus to improve glycaemic control as an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate • in combination with other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1.

HOS-098934 · has-indication-information · PDF-Seite 3

Rybelsus is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus to improve glycaemic control as an adjunct to diet and exercise • as monotherapy when metformin is considered inappropriate • in combination with other medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1.

HOS-098937 · has-interaction-information · PDF-Seite 6

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. 6 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).

HOS-098943 · has-interaction-information · PDF-Seite 30

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. 30 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).

HOS-098944 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment 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 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, Rybelsus 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 (see section 5.3).

HOS-098938 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential Women of childbearing potential have to use effective contraception during treatment 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 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, Rybelsus 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 (see section 5.3).

HOS-098942 · has-warning-information · PDF-Seite 29

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. General Semaglutide should not be used for the treatment of diabetic ketoacidosis. Diabetic ketoacidosis has been reported in insulin-dependent patients who had rapid discontinuation or dose reduction of insulin when treatment with a GLP-1 receptor agonist is started (see section 4.2). There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and semaglutide is therefore not recommended in these patients. There is no therapeutic experience with semaglutide in patients with bariatric surgery. 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. 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. Acute 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, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted. Hypoglycaemia Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with semaglutide (see section 4.2). Diabetic retinopathy In patients with diabetic retinopathy treated with insulin and subcutaneous semaglutide, an increased risk of developing diabetic retinopathy complications has been observed, a risk

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HOS-098936 · has-warning-information · PDF-Seite 4

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 General Semaglutide should not be used for the treatment of diabetic ketoacidosis. Diabetic ketoacidosis has been reported in insulin-dependent patients who had rapid discontinuation or dose reduction of insulin when treatment with a GLP-1 receptor agonist is started (see section 4.2). There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and semaglutide is therefore not recommended in these patients. There is no therapeutic experience with semaglutide in patients with bariatric surgery. 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. 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. Acute 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, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted. Hypoglycaemia Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with semaglutide (see section 4.2). Diabetic retinopathy In patients with diabetic retinopathy treated with insulin and subcutaneous semaglutide, an increased risk of developing dia

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