Vipdomet

HOS-096540 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Acute pancreatitis is a serious adverse reaction and is attributed to the alogliptin component of Vipdomet (see section 4.4). Hypersensitivity reactions, including Stevens-Johnson syndrome, anaphylactic reactions, and angioedema are serious and are attributed to the alogliptin component of Vipdomet (see section 4.4). Lactic acidosis is a serious adverse reaction, which may occur very rarely (< 1/10 000), and is attributed to the metformin component of Vipdomet (see section 4.4). Other reactions such as upper respiratory tract infections, nasopharyngitis, headache, gastroenteritis, abdominal pain, diarrhoea, vomiting, gastritis, gastroesophageal reflux disease, pruritus, rash, hypoglycaemia may occur commonly (≥ 1/100 to < 1/10) (see section 4.4) which are attributed to Vipdomet. Clinical studies conducted to support the efficacy and safety of Vipdomet involved the co-administration of alogliptin and metformin as separate tablets. However, the results of bioequivalence studies have demonstrated that Vipdomet film-coated tablets are bioequivalent to the corresponding doses of alogliptin and metformin co-administered as separate tablets. The information provided is based on a total of 7 150 patients with type 2 diabetes mellitus, including 4 201 patients treated with alogliptin and metformin, who participated in 7 phase 3 double-blind, placebo- or active-controlled clinical studies. These studies evaluated the effects of co-administered alogliptin and metformin on glycaemic control and their safety as initial combination therapy, as dual therapy in patients initially treated with metformin alone, and as add-on therapy to a thiazolidinedione or insulin. Tabulated list of adverse reactions The adverse reactions are listed by system organ class and 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); very rare (< 1/10 000), not known (cannot be estimated from available data). Table 1: Adverse reactions System organ class Frequency of adverse reactions Adverse reaction Alogliptin Metformin Vipdomet Infections and infestations upper respiratory tract infections common common nasopharyngitis common

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HOS-096536 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or history of a serious hypersensitivity reaction, including anaphylactic reaction, anaphylactic shock, and angioedema, to any dipeptidyl-peptidase-4 (DPP-4) inhibitor (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) - Acute conditions with the potential to alter renal function such as: - dehydration - severe infection - shock - Acute or chronic disease which may cause tissue hypoxia (see section 4.4) such as: - cardiac or respiratory failure - recent myocardial infarction - shock - Hepatic impairment (see section 4.4) - Acute alcohol intoxication, alcoholism (see sections 4.4 and 4.5) 4

HOS-096535 · has-indication-information · PDF-Seite 2

Vipdomet is indicated in the treatment of adult patients aged 18 years and older with type 2 diabetes mellitus: - as an adjunct to diet and exercise to improve glycaemic control in adult patients, inadequately controlled on their maximal tolerated dose of metformin alone, or those already being treated with the combination of alogliptin and metformin. - in combination with pioglitazone (i.e. triple combination therapy) as an adjunct to diet and exercise in adult patients inadequately controlled on their maximal tolerated dose of metformin and pioglitazone. - in combination with insulin (i.e. triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when insulin at a stable dose and metformin alone do not provide adequate glycaemic control. 2

HOS-096538 · has-interaction-information · PDF-Seite 7

Co-administration of 100 mg alogliptin once daily and 1 000 mg metformin hydrochloride twice daily for 6 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin or metformin. Specific pharmacokinetic drug interaction studies have not been performed with Vipdomet. The following section outlines the interactions observed with the individual components of Vipdomet (alogliptin/metformin) as reported in their respective Summary of Product Characteristics. Interactions with metformin Concomitant use not recommended Alcohol Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment. 7 Iodinated contrast agents Vipdomet 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 4.2 and 4.4). Cationic medicinal products Cationic substances that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine (400 mg twice daily) increased metformin systemic exposure (area under the curve, AUC) by 50% and Cmax by 81%. Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered. Combination 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, angiotensin- converting enzyme (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. Medicinal products with intrinsic hyperglycaemic activity Glucocorticoids (given by systemic and local routes), beta-2-agonists and diuretics (see also section 4.4) 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. I

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HOS-096539 · has-pregnancy-information · PDF-Seite 9

Pregnancy There are no data from the use of Vipdomet in pregnant women. Studies in pregnant rats with alogliptin plus metformin as combination treatment have shown reproductive toxicity (see section 5.3) at approximately 5-20 times (for metformin and alogliptin respectively) the human exposure at the recommended dose. Vipdomet should not be used during pregnancy. Risk related to alogliptin There are no data from the use of alogliptin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Risk related to metformin A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses (see section 5.3). Breast-feeding No studies in lactating animals have been conducted with the combined active substances of Vipdomet. In studies performed with the individual active substances, both alogliptin and metformin were excreted in the milk of lactating rats. It is unknown whether alogliptin is excreted in human milk. Metformin is excreted in human milk in small amounts. A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Vipdomet therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility The effect of Vipdomet on fertility in humans has not been studied. No adverse effects on fertility were observed in animal studies conducted with alogliptin or with metformin (see section 5.3). 9

HOS-096537 · has-warning-information · PDF-Seite 5

General Vipdomet should not be used in patients with type 1 diabetes mellitus. Vipdomet is not a substitute for insulin in insulin-requiring patients. Lactic acidosis Lactic acidosis, a very 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 diarrhoea or vomiting, fever, heat, reduced fluid intake) Vipdomet 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 nonsteroidal anti-inflammatory drugs (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 on 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 Vipdomet 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 episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed. Administration of iodinated contrast agents Intravascular administration of iodinated contrast media may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Vipdomet should be discont

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