Ristfor · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-155051 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile There have been no therapeutic clinical studies conducted with Ristfor tablets however bioequivalence of Ristfor with co-administered sitagliptin and metformin has been demonstrated (see section 5.2). Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea (13.8 %) and insulin (10.9 %). Tabulated list of adverse reactions Sitagliptin and metformin Adverse reactions are listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1). 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); very rare (< 1/10 000) and not known (cannot be estimated from the available data). 8 Table 1: The frequency of adverse reactions identified from placebo-controlled clinical studies of sitagliptin and metformin alone, and post-marketing experience Adverse reaction Frequency of adverse reaction Blood and lymphatic system disorders thrombocytopenia Rare Immune system disorders hypersensitivity reactions including anaphylactic Frequency not known responses*,† Metabolism and nutrition disorders hypoglycaemia† Common Vitamin B12 decrease/deficiency† Common Nervous system disorders somnolence Uncommon Respiratory, thoracic and mediastinal disorders interstitial lung disease* Frequency not known Gastrointestinal disorders diarrhoea Uncommon nausea Common flatulence Common constipation Uncommon upper abdominal pain Uncommon vomiting Common acute pancr

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HOS-155047 · has-contraindication-information · PDF-Seite 4

Ristfor is contraindicated in patients with: - hypersensitivity to the active substances or to any of the excipients listed in section 6.1 (see sections 4.4 and 4.8); - any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); - diabetic pre-coma; - severe renal failure (GFR< 30 mL/min) (see section 4.4); - acute conditions with the potential to alter renal function such as: - dehydration, - severe infection, - shock, - intravascular administration of iodinated contrast agents (see section 4.4); - acute or chronic disease which may cause tissue hypoxia such as: - cardiac or respiratory failure, - recent myocardial infarction, - shock; - hepatic impairment; - acute alcohol intoxication, alcoholism; - breast-feeding.

HOS-155046 · has-indication-information · PDF-Seite 2

For adult patients with type 2 diabetes mellitus: Ristfor is indicated as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin. Ristfor is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea. Ristfor is indicated as triple combination therapy with a peroxisome proliferator-activated receptor gamma (PPAR) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPAR agonist. Ristfor is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycaemic control. 2

HOS-155049 · has-interaction-information · PDF-Seite 6

Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1 000 mg twice daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes. Pharmacokinetic drug interaction studies with Ristfor have not been performed; however, such studies have been conducted with the individual active substances, sitagliptin and metformin. Concomitant use not recommended Alcohol Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment. Iodinated contrast agents Ristfor must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable (see sections 4.3 and 4.4). 6 Combinations requiring precautions for use Some medicinal products can adversely affect renal function, which may increase the risk of lactic acidosis, e.g., NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary. Concomitant use of medicinal products that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when such products are co-administered. Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation. ACE-inhibitors may decrease the blood glucose levels. If necessary, the dos

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HOS-155050 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses of sitagliptin (see section 5.3). A limited amount of data suggests the use of metformin in pregnant women is not associated with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3). Ristfor should not be used during pregnancy. If a patient wishes to become pregnant or if a pregnancy occurs, treatment should be discontinued and the patient switched to insulin treatment as soon as possible. Breast-feeding No studies in lactating animals have been conducted with the combined active substances of this medicinal product. In studies performed with the individual active substances, both sitagliptin and metformin are excreted in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether sitagliptin is excreted in human milk. Ristfor must therefore not be used in women who are breast-feeding (see section 4.3). Fertility Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking.

HOS-155048 · has-warning-information · PDF-Seite 4

General Ristfor should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis. 4 Acute pancreatitis Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Ristfor and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Ristfor should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Lactic acidosis Lactic acidosis, a rare but serious metabolic complication, most often occurs at acute worsening of renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis. In case of dehydration (severe vomiting, diarrhoea, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended. Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see sections 4.3 and 4.5). Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35), increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio. Patients with known or suspected mitochondrial diseases: In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like

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