Xultophy · 4.3 Contraindications · 1

HOS-096516 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The Xultophy clinical development programme included approximately 1 900 patients treated with Xultophy. The most frequently reported adverse reactions during treatment with Xultophy were hypoglycaemia and gastrointestinal adverse reactions (see section ‘Description of selected adverse reactions’ below). Tabulated list of adverse reactions Adverse reactions associated with Xultophy are given below, 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 Adverse reactions reported in phase 3 controlled studies MedDRA System organ class Frequency Adverse reaction Immune system disorders Uncommon Urticaria Uncommon Hypersensitivity Unknown Anaphylactic reaction Metabolism and nutrition disorders Very common Hypoglycaemia Common Decreased appetite Uncommon Dehydration Common Dizziness Nervous system disorders Uncommon Dysgeusia Gastrointestinal disorders Common Nausea, diarrhoea, vomiting, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux disease, abdominal distension Uncommon Eructation, flatulence Unknown Pancreatitis (including necrotising pancreatitis) Delayed gastric emptying† Intestinal obstruction† Hepatobiliary disorders Uncommon Cholelithiasis Uncommon Cholecystitis Skin and subcutaneous tissue Uncommon Rash disorders Uncommon

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HOS-096512 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to either or both active substances or to any of the excipients listed in section 6.1.

HOS-096511 · has-indication-information · PDF-Seite 2

Xultophy 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 in addition to other oral medicinal products for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control, and the populations studied, see sections 4.4, 4.5 and 5.1.

HOS-096514 · has-interaction-information · PDF-Seite 6

Pharmacodynamic interactions Interaction studies with Xultophy have not been performed. A number of substances affect glucose metabolism and may require dose adjustment of Xultophy. The following substances may reduce the Xultophy requirement: Antidiabetic medicinal products, monoamine oxidase inhibitors (MAOI), beta-blockers, angiotensin converting enzyme (ACE) inhibitors, salicylates, anabolic steroids and sulfonamides. The following substances may increase the Xultophy requirement: Oral contraceptives, thiazides, glucocorticoids, thyroid hormones, sympathomimetics, growth hormones and danazol. Beta-blockers may mask the symptoms of hypoglycaemia. Octreotide/lanreotide may either increase or decrease the Xultophy requirement. Alcohol may intensify or reduce the hypoglycaemic effect of Xultophy. Pharmacokinetic interactions In vitro data suggest that the potential for pharmacokinetic drug interactions related to CYP interaction and protein binding is low for both liraglutide and insulin degludec. The small delay of gastric emptying with liraglutide may influence absorption of concomitantly administered oral medicinal products. Interaction studies did not show any clinically relevant delay of absorption. Warfarin and other coumarin derivatives No interaction study has been performed. A clinically relevant interaction with active substances with poor solubility or with narrow therapeutic index such as warfarin cannot be excluded. Upon initiation of Xultophy treatment in patients on warfarin or other coumarin derivatives more frequent monitoring of INR (International Normalised Ratio) is recommended. 6 Paracetamol Liraglutide did not change the overall exposure of paracetamol following a single dose of 1 000 mg. Paracetamol Cmax was decreased by 31% and median tmax was delayed up to 15 min. No dose adjustment for concomitant use of paracetamol is required. Atorvastatin Liraglutide did not change the overall exposure of atorvastatin to a clinical relevant degree following single dose administration of atorvastatin 40 mg. Therefore, no dose adjustment of atorvastatin is required when given with liraglutide. Atorvastatin Cmax was decreased by 38% and median tmax was delayed from 1 h to 3 h with liraglutide. Griseofulvin Liraglutide did not change the overall exposure of griseofulvin following administration of a single dose of griseofulvin 500 mg. Griseofulvin Cmax increased by 37% while median tma

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HOS-096515 · has-pregnancy-information · PDF-Seite 7

Pregnancy There is no clinical experience with the use of Xultophy, insulin degludec or liraglutide in pregnant women. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Xultophy should be discontinued. Animal reproduction studies with insulin degludec have not revealed any differences between insulin degludec and human insulin regarding embryotoxicity and teratogenicity. Animal studies with liraglutide have shown reproductive toxicity, see section 5.3. The potential risk for humans is unknown. Breast-feeding There is no clinical experience with the use of Xultophy during breast-feeding. It is not known whether insulin degludec or liraglutide is excreted in human milk. Because of lack of experience, Xultophy should not be used during breast-feeding. In rats, insulin degludec was secreted in milk; the concentration in milk was lower than in plasma. Animal studies have shown that the transfer of liraglutide and metabolites of close structural relationship into milk was low. Non-clinical studies with liraglutide have shown a treatment-related reduction of neonatal growth in suckling rat pups (see section 5.3). 7 Fertility There is no clinical experience with Xultophy in relation to fertility. Animal reproduction studies with insulin degludec have not revealed any adverse effects on fertility. Apart from a slight decrease in the number of live implants, animal studies with liraglutide did not indicate harmful effects with respect to fertility.

HOS-096513 · has-warning-information · PDF-Seite 4

Xultophy should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Hypoglycaemia Hypoglycaemia may occur if the dose of Xultophy is higher than required. Omission of a meal or unplanned strenuous physical exercise may lead to hypoglycaemia. In combination with sulfonylurea, the risk of hypoglycaemia may be lowered by a reduction in the dose of sulfonylurea. Concomitant diseases in the kidney, liver or diseases affecting the adrenal, pituitary or thyroid gland may require changes of the Xultophy dose. Patients whose blood glucose control is greatly improved (e.g. by intensified therapy) may experience a change in their usual warning symptoms of hypoglycaemia and must be advised accordingly. Usual warning symptoms (see section 4.8) of hypoglycaemia may disappear in patients with long-standing diabetes. The prolonged effect of Xultophy may delay recovery from hypoglycaemia. Hyperglycaemia Inadequate dosing and/or discontinuation of antidiabetic treatment may lead to hyperglycaemia and potentially to hyperosmolar coma. In case of discontinuation of Xultophy, ensure that instruction for initiation of alternative antidiabetic treatment is followed. Furthermore, concomitant illness, especially infections, may lead to hyperglycaemia and thereby cause an increased requirement for antidiabetic treatment. Usually, the first symptoms of hyperglycaemia develop gradually over a period of hours or days. They include thirst, increased frequency of urination, nausea, vomiting, drowsiness, flushed dry skin, dry mouth, and loss of appetite as well as acetone odour of breath. Administration of rapid-acting insulin should be considered in situations of severe hyperglycaemia. Untreated hyperglycaemic events eventually lead to hyperosmolar coma/diabetic ketoacidosis, which is potentially lethal. Skin and subcutaneous tissue disorders Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site from an affected to an unaffected area, and dose adjustment of antidiabetic medications may be considered. Combin

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