NovoNorm · 4.8 Undesirable effects · 2

HOS-083662 · has-adverse-reaction-information · PDF-Seite 27

Summary of the safety profile The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress. Tabulated list of adverse reactions Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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). Immune system disorders Allergic reactions* Very rare Metabolism and nutrition Hypoglycaemia Common disorders Hypoglycaemic coma and Not known hypoglycaemic unconsciousness Eye disorders Refraction disorder* Very rare Cardiac disorders Cardiovascular disease Rare Gastrointestinal disorders Abdominal pain, diarrhoea Common Vomiting, constipation Very rare Nausea Not known Hepatobiliary disorders Abnormal hepatic function, Very rare increased liver enzymes* Skin and subcutaneous tissue Hypersensitivity* Not known disorders * see section Description of selected adverse reactions below Description of selected adverse reactions 27 Allergic reactions Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis. Refraction disorders Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials. Abnormal hepatic function, increased liver enzymes Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes. In very rare cases, severe hepati

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HOS-083656 · has-adverse-reaction-information · PDF-Seite 17

Summary of the safety profile The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress. Tabulated list of adverse reactions Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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). Immune system disorders Allergic reactions* Very rare Metabolism and nutrition Hypoglycaemia Common disorders Hypoglycaemic coma and Not known hypoglycaemic unconsciousness Eye disorders Refraction disorder* Very rare Cardiac disorders Cardiovascular disease Rare Gastrointestinal disorders Abdominal pain, diarrhoea Common Vomiting, constipation Very rare Nausea Not known Hepatobiliary disorders Abnormal hepatic function, Very rare increased liver enzymes* Skin and subcutaneous tissue Hypersensitivity* Not known disorders * see section Description of selected adverse reactions below Description of selected adverse reactions 17 Allergic reactions Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis. Refraction disorders Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials. Abnormal hepatic function, increased liver enzymes Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increased liver enzymes.

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HOS-083650 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most frequently reported adverse reactions are changes in blood glucose levels, i.e. hypoglycaemia. The occurrence of such reactions depends on individual factors, such as dietary habits, dosage, exercise and stress. Tabulated list of adverse reactions Based on the experience with repaglinide and with other hypoglycaemic medicinal products the following adverse reactions have been seen: Frequencies are defined as: 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). Immune system disorders Allergic reactions* Very rare Metabolism and nutrition Hypoglycaemia Common disorders Hypoglycaemic coma and Not known hypoglycaemic unconsciousness Eye disorders Refraction disorder* Very rare Cardiac disorders Cardiovascular disease Rare Gastrointestinal disorders Abdominal pain, diarrhoea Common Vomiting, constipation Very rare Nausea Not known Hepatobiliary disorders Abnormal hepatic Very rare function, increased liver enzymes* Skin and subcutaneous tissue Hypersensitivity* Not known disorders * see section Description of selected adverse reactions below Description of selected adverse reactions Allergic reactions 7 Generalised hypersensitivity reactions (e.g. anaphylactic reaction), or immunological reactions such as vasculitis. Refraction disorders Changes in blood glucose levels have been known to result in transient visual disturbances, especially at the commencement of treatment. Such disturbances have only been reported in very few cases after initiation of repaglinide treatment. No such cases have led to discontinuation of repaglinide treatment in clinical trials. Abnormal hepatic function, increased liver enzymes Isolated cases of increased liver enzymes have been reported during treatment with repaglinide. Most cases were mild and transient, and very few patients discontinued treatment due to increas

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HOS-083646 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1. • Diabetes mellitus type 1, C-peptide negative. • Diabetic ketoacidosis, with or without coma. • Severe hepatic function disorder. • Concomitant use of gemfibrozil (see section 4.5).

HOS-083658 · has-contraindication-information · PDF-Seite 23

• Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1. • Diabetes mellitus type 1, C-peptide negative. • Diabetic ketoacidosis, with or without coma. • Severe hepatic function disorder. • Concomitant use of gemfibrozil (see section 4.5). 23

HOS-083652 · has-contraindication-information · PDF-Seite 13

• Hypersensitivity to repaglinide or to any of the excipients listed in section 6.1. • Diabetes mellitus type 1, C-peptide negative. • Diabetic ketoacidosis, with or without coma. • Severe hepatic function disorder. • Concomitant use of gemfibrozil (see section 4.5).

HOS-083645 · has-indication-information · PDF-Seite 2

Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone. Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.

HOS-083657 · has-indication-information · PDF-Seite 22

Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone. Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.

HOS-083651 · has-indication-information · PDF-Seite 12

Repaglinide is indicated in adults with type 2 diabetes mellitus whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise. Repaglinide is also indicated in combination with metformin in adults with type 2 diabetes mellitus who are not satisfactorily controlled on metformin alone. Treatment should be initiated as an adjunct to diet and exercise to lower the blood glucose in relation to meals.

HOS-083660 · has-interaction-information · PDF-Seite 24

A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician: In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 24 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of repaglinide, may be altered by substances which influence these cytochrome P-450 enzymes via inhibition or induction. Special care should be taken when inhibitors of both CYP2C8 and 3A4 are co-administered simultaneously with repaglinide. Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below). The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketokonazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs, octreotide, alcohol, and anabolic steroids. Co-administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC 8.1-fold and Cmax 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7 hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use of gemfibrozil and repaglinide is contraindicated (see section 4.3). Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, Cmax and t½ (1.6-fold, 1.4-fold and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety profile of this combinati

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HOS-083648 · has-interaction-information · PDF-Seite 4

A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician: In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of 4 repaglinide, may be altered by substances which influence these cytochrome P-450 enzymes via inhibition or induction. Special care should be taken when inhibitors of both CYP2C8 and 3A4 are co-administered simultaneously with repaglinide. Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below). The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketokonazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs, octreotide, alcohol, and anabolic steroids. Co-administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC 8.1-fold and Cmax 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7 hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use of gemfibrozil and repaglinide is contraindicated (see section 4.3). Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, Cmax and t½ (1.6-fold, 1.4-fold and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety profile of this combinatio

Auszug; vollständigen Abschnitt im Original lesen.

HOS-083654 · has-interaction-information · PDF-Seite 14

A number of medicinal products are known to influence repaglinide metabolism. Possible interactions should therefore be taken into account by the physician: In vitro data indicate that repaglinide is metabolised predominantly by CYP2C8, but also by CYP3A4. Clinical data in healthy volunteers support CYP2C8 as being the most important enzyme involved in repaglinide metabolism with CYP3A4 playing a minor role, but the relative contribution of CYP3A4 can be increased if CYP2C8 is inhibited. Consequently metabolism, and by that clearance of 14 repaglinide, may be altered by substances which influence these cytochrome P-450 enzymes via inhibition or induction. Special care should be taken when inhibitors of both CYP2C8 and 3A4 are co-administered simultaneously with repaglinide. Based on in vitro data, repaglinide appears to be a substrate for active hepatic uptake (organic anion transporting protein OATP1B1). Substances that inhibit OATP1B1 may likewise have the potential to increase plasma concentrations of repaglinide, as has been shown for ciclosporin (see below). The following substances may enhance and/or prolong the hypoglycaemic effect of repaglinide: Gemfibrozil, clarithromycin, itraconazole, ketokonazole, trimethoprim, ciclosporin, deferasirox, clopidogrel, other antidiabetic substances, monoamine oxidase inhibitors (MAOI), non selective beta blocking substances, angiotensin converting enzyme (ACE)-inhibitors, salicylates, NSAIDs, octreotide, alcohol, and anabolic steroids. Co-administration of gemfibrozil (600 mg twice daily), an inhibitor of CYP2C8, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC 8.1-fold and Cmax 2.4-fold in healthy volunteers. Half-life was prolonged from 1.3 hr to 3.7 hr, resulting in possibly enhanced and prolonged blood glucose-lowering effect of repaglinide, and plasma repaglinide concentration at 7 hr was increased 28.6-fold by gemfibrozil. The concomitant use of gemfibrozil and repaglinide is contraindicated (see section 4.3). Co-administration of trimethoprim (160 mg twice daily), a moderate CYP2C8 inhibitor, and repaglinide (a single dose of 0.25 mg) increased the repaglinide AUC, Cmax and t½ (1.6-fold, 1.4-fold and 1.2-fold respectively) with no statistically significant effects on the blood glucose levels. This lack of pharmacodynamic effect was observed with a sub-therapeutic dose of repaglinide. Since the safety profile of this combinati

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HOS-083661 · has-pregnancy-information · PDF-Seite 26

Pregnancy There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy. Breast-feeding 26 There are no studies in breast-feeding women. Repaglinide should not be used in breast-feeding women. Fertility Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.

HOS-083649 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy. Breast-feeding There are no studies in breast-feeding women. Repaglinide should not be used in breast-feeding women. 6 Fertility Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.

HOS-083655 · has-pregnancy-information · PDF-Seite 16

Pregnancy There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during pregnancy. Breast-feeding 16 There are no studies in breast-feeding women. Repaglinide should not be used in breast-feeding women. Fertility Data from animal studies investigating effects on embryofetal and offspring development as well as excretion in milk is described in section 5.3.

HOS-083659 · has-warning-information · PDF-Seite 24

General Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction. When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis. Hypoglycaemia Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia. Combination with insulin secretagogues The blood glucose-lowering effect of oral hypoglycaemic medicinal products decreases in many patients over time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary failure, where the medicinal product is ineffective in an individual patient when first given. Adjustment of dose and adherence to diet and exercise should be assessed before classifying a patient as a secondary failure. Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in case of secondary failure to insulin secretagogues has not been investigated in clinical trials. Trials investigating the combination with other insulin secretagogues have not been performed. Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies. Combination with metformin Combination treatment with metformin is associated with an increased risk of hypoglycaemia. Acute coronary syndrome The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1. Concomitant use Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.

HOS-083653 · has-warning-information · PDF-Seite 13

13 General Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction. When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis. Hypoglycaemia Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia. Combination with insulin secretagogues The blood glucose-lowering effect of oral hypoglycaemic medicinal products decreases in many patients over time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary failure, where the medicinal product is ineffective in an individual patient when first given. Adjustment of dose and adherence to diet and exercise should be assessed before classifying a patient as a secondary failure. Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in case of secondary failure to insulin secretagogues has not been investigated in clinical trials. Trials investigating the combination with other insulin secretagogues have not been performed. Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies. Combination with metformin Combination treatment with metformin is associated with an increased risk of hypoglycaemia. Acute coronary syndrome The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1. Concomitant use Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.

HOS-083647 · has-warning-information · PDF-Seite 3

3 General Repaglinide should only be prescribed if poor blood glucose control and symptoms of diabetes persist despite adequate attempts at dieting, exercise and weight reduction. When a patient stabilised on any oral hypoglycaemic medicinal product is exposed to stress such as fever, trauma, infection or surgery, a loss of glycaemic control may occur. At such times, it may be necessary to discontinue repaglinide and treat with insulin on a temporary basis. Hypoglycaemia Repaglinide, like other insulin secretagogues, is capable of producing hypoglycaemia. Combination with insulin secretagogues The blood glucose-lowering effect of oral hypoglycaemic medicinal products decreases in many patients over time. This may be due to progression of the severity of the diabetes or to diminished responsiveness to the medicinal product. This phenomenon is known as secondary failure, to distinguish it from primary failure, where the medicinal product is ineffective in an individual patient when first given. Adjustment of dose and adherence to diet and exercise should be assessed before classifying a patient as a secondary failure. Repaglinide acts through a distinct binding site with a short action on the β-cells. Use of repaglinide in case of secondary failure to insulin secretagogues has not been investigated in clinical trials. Trials investigating the combination with other insulin secretagogues have not been performed. Combination with Neutral Protamine Hagedorn (NPH) insulin or thiazolidinediones Trials of combination therapy with NPH insulin or thiazolidinediones have been performed. However, the benefit risk profile remains to be established when comparing to other combination therapies. Combination with metformin Combination treatment with metformin is associated with an increased risk of hypoglycaemia. Acute coronary syndrome The use of repaglinide might be associated with an increased incidence of acute coronary syndrome (e.g. myocardial infarction), see sections 4.8 and 5.1. Concomitant use Repaglinide should be used with caution or be avoided in patients receiving medicinal products which influence repaglinide metabolism (see section 4.5). If concomitant use is necessary, careful monitoring of blood glucose and close clinical monitoring should be performed.