LINAGLIPTIN/METFORMIN HYDROCHLORIDE

Posology Adults with normal renal function (GFR ≥ 90 mL/min) The dose of antihyperglycaemic therapy with Linagliptin/metformin should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability, while not exceeding the maximum recommended daily dose of 5 mg linagliptin plus 2 000 mg of metformin hydrochloride.

5 mg twice daily (5 mg total daily dose) plus the dose of metformin already being taken. Patients switching from co-administration of linagliptin and metformin For patients switching from co-administration of linagliptin and metformin, Linagliptin/metformin should be initiated at the dose of linagliptin and metformin already being taken.

5 mg twice daily (5 mg total daily dose) and a dose of metformin similar to the dose already being taken. 4). 5 mg twice daily (5 mg total daily dose) and a dose of metformin similar to the dose already being taken. 4). 5 mg linagliptin plus 1 000 mg metformin hydrochloride.

Special populations Elderly As metformin is excreted by the kidney, Linagliptin/metformin should be used with caution as age increases. 4). Renal impairment A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter.

g. every 3-6 months. 4) should be reviewed before considering initiation of metformin in patients with GFR< 60 mL/min. If no adequate strength of Linagliptin/metformin is available, individual monocomponents should be used instead of the fixed dose combination.

Table 1:

Posology for renally impaired patients GFR mL/min Metformin Linagliptin 60-89 Maximum daily dose is 3 000 mg. Dose reduction may be considered in relation to declining renal function. No dose adjustment 45-59 Maximum daily dose is 2 000 mg The starting dose is at most half of the maximum dose.

No dose adjustment 30-44 Maximum daily dose is 1 000 mg. The starting dose is at most half of the maximum dose. 2). Clinical experience with Linagliptin/metformin in patients with hepatic impairment is lacking. 2). Therefore, treatment of children and adolescents with linagliptin is not recommended.

Linagliptin has not been studied in paediatric patients under 10 years of age. Method of administration Linagliptin/metformin should be taken twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.

5 mg twice daily (or its bioequivalent of 5 mg once daily) in combination with metformin has been evaluated in over 6 800 patients with type 2 diabetes mellitus. 5 mg linagliptin twice daily (or its bioequivalent of 5 mg linagliptin once daily) in combination with metformin for ≥ 12/24 weeks.

0%). 9%). 4%). Hypoglycaemia may occur when Linagliptin/metformin is administered together with sulphonylurea ( ≥ 1 case per 10 patients). Tabulated list of adverse reactions Adverse reactions reported in all clinical trials with the Linagliptin+metformin combination or the use of the monocomponents (linagliptin or metformin) in clinical trials or from post-marketing experience are shown below according to system organ class.

Adverse reactions previously reported with one of the individual active substances may be potential adverse reactions with Linagliptin/metformin, even if not observed in clinical trials with this medicinal product. The adverse reactions are listed 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), or very rare (< 1/10 000) and not known (cannot be estimated from the available data).

g. bronchial hyperreactivity) uncommon Metabolism and nutrition disorders Hypoglycaemia 1 very common Lactic acidosis § very rare Vitamin B12 decrease/deficiency §, † common Nervous system disorders Taste disturbance § common Respiratory, thoracic and mediastinal disorders Cough uncommon Gastrointestinal disorders Decreased appetite uncommon Diarrhoea common Nausea common Pancreatitis rare # Vomiting uncommon Constipation 2 uncommon Abdominal pain § very common Hepatobiliary disorders Liver function disorders 2 uncommon Hepatitis § very rare Skin and subcutaneous tissue disorders Angioedema rare Urticaria rare Erythema § very rare Rash uncommon Pruritus uncommon Bullous pemphigoid rare # Investigations Amylase increased uncommon Lipase increased* common * Based on lipase elevations > 3 × ULN observed in clinical trials # Based on Linagliptin cardiovascular and renal safety study (CARMELINA), see also below § Identified adverse reactions of metformin monotherapy.

General Linagliptin/metformin should not be used in patients with type 1 diabetes. Hypoglycaemia When linagliptin was added to a sulphonylurea on a background of metformin, the incidence of hypoglycaemia was increased over that of placebo.

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when Linagliptin/metformin is used in combination with a sulphonylurea and/or insulin. 2). Hypoglycaemia is not identified as adverse reaction for linagliptin, metformin, or linagliptin plus metformin.

In clinical trials, the incidence rates of hypoglycaemia were comparably low in patients taking linagliptin in combination with metformin or metformin alone. 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 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. 5). Patients and/or care-givers should be informed of the risk of lactic acidosis.

Lactic acidosis is characterised by acidotic dyspnea, 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.

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.

1. • 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.

• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock. 5).