Metformin and Linagliptin

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months

Posology:

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin in patients with GFR <60 ml/min.

Posology:

The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

A limited amount of data suggests that 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 reproductive toxicity.

Non-clinical reproduction studies did not indicate an additive teratogenic effect attributed to the coadministration of linagliptin and metformin.

Metformin/linagliptin should not be used during pregnancy. If the patient plans to become pregnant, or if pregnancy occurs, treatment with metformin/linagliptin should be discontinued and switched to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

Studies in animals have shown excretion of both metformin and linagliptin into milk in lactating rats. Metformin is excreted in human milk in small amounts. It is not known whether linagliptin is excreted into human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from metformin/linagliptin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of metformin/linagliptin on human fertility has not been studied. No adverse effects of linagliptin on fertility were observed in male or female rats.

Metformin/linagliptin has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia when metformin/linagliptin is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).

Summary of the safety profile

The safety of linagliptin 2.5 mg twice daily (or its bioequivalent of 5 mg once daily) in combination with metformin has been evaluated in over 6800 patients with type 2 diabetes mellitus. In placebocontrolled studies, more than 1800 patients were treated with the therapeutic dose of either 2.5 mg linagliptin twice daily (or its bioequivalent of 5 mg linagliptin once daily) in combination with metformin for ≥12/24 weeks.

In the pooled analysis of the seven placebo-controlled trials, the overall incidence of adverse events in patients treated with placebo and metformin was comparable to that seen with linagliptin 2.5 mg and metformin (54.3 and 49.0%). Discontinuation of therapy due to adverse events was comparable in patients who received placebo and metformin to patients treated with linagliptin and metformin (3.8% and 2.9%).

The most frequently reported adverse reaction for linagliptin plus metformin was diarrhoea (1.6%) with a comparable rate on metformin plus placebo (2.4%).

Hypoglycaemia may occur when metformin/linagliptin is administered together with sulphonylurea (≥1 case per 10 patients).

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 metformin/linagliptin, 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).

Adverse reactions reported in patients who received linagliptin+metformin alone (as mono-components or in combination) or as add-on to other anti-diabetic therapies in clinical trial and from post-marketing experience:

^* Based on lipase elevations >3xULN observed in clinical trials
^# Based on Linagliptin cardiovascular and renal safety study (CARMELINA), see also below
^§ Adverse reactions reported in patients who received metformin as monotherapy and that were not observed in patients receiving metformin/linagliptin. Refer to Summary of Product Characteristics for metformin for additional information
¹ Adverse reaction observed in combination of metformin/linagliptin with sulphonylurea
² Adverse reaction observed in combination of metformin/linagliptin with insulin

Description of selected adverse reactions

Hypoglycaemia

In one study linagliptin was given as add-on to metformin plus sulphonylurea. When linagliptin and metformin were administered in combination with a sulphonylurea, hypoglycaemia was the most frequently reported adverse event (linagliptin plus metformin plus sulphonylurea 23.9% and 16.0% in placebo plus metformin plus sulphonylurea).

When linagliptin and metformin were administered in combination with insulin, hypoglycaemia was the most frequently reported adverse event, but occurred at comparable rate when placebo and metformin were combined with insulin (linagliptin plus metformin plus insulin 29.5% and 30.9% in the placebo plus metformin plus insulin group) with a low rate of severe (requiring assistance) episodes (1.5% and 0.9%).

Other adverse reactions

Gastrointestinal disorders such as, nausea, vomiting, diarrhoea and decreased appetite and abdominal pain occur most frequently during initiation of therapy with metformin/linagliptin or metformin hydrochloride and resolve spontaneously in most cases. For prevention, it is recommended that metformin/linagliptin be taken during or after meals. A slow increase in dose of metformin hydrochloride may also improve gastrointestinal tolerability.

Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g. megaloblastic anaemia).

Linagliptin cardiovascular and renal safety study (CARMELINA)

The CARMELINA study evaluated the cardiovascular and renal safety of linagliptin versus placebo in patients with type 2 diabetes and with increased CV risk evidenced by a history of established macrovascular or renal disease. The study included 3494 patients treated with linagliptin (5 mg) and 3485 patients treated with placebo. Both treatments were added to standard of care targeting regional standards for HbA1c and CV risk factors. The overall incidence of adverse events and serious adverse events in patients receiving linagliptin was similar to that in patients receiving placebo. Safety data from this study was in line with previous known safety profile of linagliptin.

In the treated population, severe hypoglycaemic events (requiring assistance) were reported in 3.0% of patients on linagliptin and in 3.1% on placebo. Among patients who were using sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.0% in linagliptin-treated patients and 1.7% in placebo treated patients. Among patients who were using insulin at baseline, the incidence of severe hypoglycaemia was 4.4% in linagliptin-treated patients and 4.9% in placebo treated patients.

In the overall study observation period adjudicated acute pancreatitis was reported in 0.3% of patients treated with linagliptin and in 0.1% of patients treated with placebo.

In the CARMELINA study, bullous pemphigoid was reported in 0.2% of patients treated with linagliptin and in no patient treated with placebo.