Metformin and Saxagliptin

No dose adjustment is recommended for patients with mild renal impairment (GFR 60-89 mL/min).

A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at 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. The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of saxagliptin/metformin in patients with GFR <60 mL/min.

If no adequate strength of the fixed dose combination is available, individual monocomponents should be used instead of the fixed dose combination.

Dosage in patients with renal impairment:

The use of saxagliptin/metformin or saxagliptin has not been studied in pregnant women. Studies in animals have shown reproductive toxicity at high doses of saxagliptin alone or in combination with metformin. The potential risk for humans is unknown. A limited amount of data suggest 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. This medicinal product should not be used during pregnancy. If the patient wishes to become pregnant, or if a pregnancy occurs, treatment with this medicinal product should be discontinued and switched to insulin treatment as soon as possible.

Studies in animals have shown excretion of both saxagliptin and/or metabolite and metformin in milk. It is unknown whether saxagliptin is excreted in human milk, but metformin is excreted in human milk in small amounts. This medicinal product must therefore not be used in women who are breast-feeding.

Fertility

The effect of saxagliptin on fertility in humans has not been studied. Effects on fertility were observed in male and female rats at high doses producing overt signs of toxicity. For metformin, studies in animals have not shown reproductive toxicity.

Saxagliptin or metformin has a negligible influence on the ability to drive and use machines. When driving or using machines, it should be taken into account that dizziness has been reported in studies with saxagliptin. In addition, patients should be alerted to the risk of hypoglycaemia when metformin/saxagliptin is used in combination with other antidiabetic medicinal products known to cause hypoglycaemia (e.g. insulin, sulphonylureas).

There have been no therapeutic clinical trials conducted with saxagliptin/metformin fixed dose combination, however, bioequivalence of it with co-administered saxagliptin and metformin has been demonstrated.

Saxagliptin

Summary of the safety profile

There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with saxagliptin, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control. In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes have been treated with saxagliptin.

In a pooled analysis of 1,681 patients with type 2 diabetes, including 882 patients treated with saxagliptin 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of AEs in patients treated with saxagliptin 5 mg was similar to placebo. Discontinuation of therapy due to AEs was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).

Tabulated list of adverse reactions

Adverse reactions reported in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥2% of patients treated with saxagliptin 5 mg and ≥1% more frequently compared to placebo are shown in Table 1.

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), not known (cannot be estimated from the available data).

Table 1. Frequency of adverse reactions by system organ class:

¹ Includes saxagliptin in add-on to metformin and initial combination with metformin.
² Only in the initial combination therapy.

Postmarketing experience from clinical trials and spontaneous reports

Table 2 shows additional adverse reactions which have been reported in postmarketing experience with saxagliptin. The frequencies are based on the experience from clinical trials.

Table 2. Frequency of additional adverse reactions by system organ class:

¹ Frequency estimates are based on the pooled analysis of the saxagliptin monotherapy, add-on to metformin and initial combination with metformin, add-on to sulphonylurea and add-on to thiazolidinedione clinical trials.
² These reactions were also identified in the pre-approval clinical trials, but do not meet the criteria for Table 1.

SAVOR trial results

The SAVOR trial included 8240 patients treated with saxagliptin 5 mg or 2.5 mg once daily and 8173 patients on placebo. The overall incidence of AEs in patients treated with saxagliptin in this trial was similar to placebo (72.5% versus 72.2%, respectively).

The incidence of adjudicated pancreatitis events was 0.3% in both saxagliptin-treated patients and placebo-treated patients in the intent-to-treat population.

The incidence of hypersensitivity reactions was 1.1% in both saxagliptin-treated patients and placebotreated patients.

The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in subjects treated with saxagliptin and 14.8% among patients treated with placebo. The percent of subjects with reported on-treatment events of major hypoglycaemia (defined as an event that required assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively). The increased risk of overall hypoglycaemia and major hypoglycaemia observed in the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not in subjects on insulin or metformin monotherapy at baseline. The increased risk of overall and major hypoglycaemia was primarily observed in subjects with A1C <7% at baseline.

Decreased lymphocyte counts were reported in 0.5% of saxagliptin-treated patients and 0.4% of placebo-treated patients.

Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 95% CI 1.07, 1.51); P = 0.007].

Description of selected adverse reactions

AEs, considered by the investigator to be at least possibly drug-related and reported in at least two more patients treated with saxagliptin 5 mg compared to control, are described below by treatment regimen.

As monotherapy: dizziness (common) and fatigue (common).

As add-on to metformin: dyspepsia (common) and myalgia (common).

As initial combination with metformin: gastritis (common), arthralgia* (uncommon), myalgia (uncommon), and erectile dysfunction (uncommon).

As add-on to metformin and a sulphonylurea: dizziness (common), fatigue (common) and flatulence (common).

^* Arthralgia has also been reported during postmarketing surveillance.

Hypoglycaemia

Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required. The incidence of reported hypoglycaemia for saxagliptin 5 mg versus placebo given as add-on therapy to metformin was 5.8% versus 5%. The incidence of reported hypoglycaemia was 3.4% in treatment-naive patients given saxagliptin 5 mg plus metformin and 4.0% in patients given metformin alone. When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo.

When used as add-on to metformin plus a sulphonylurea, the overall incidence of reported hypoglycaemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo.

Investigations

Across clinical studies, the incidence of laboratory AEs was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μL, a mean decrease of approximately 100 cells/μL relative to placebo was observed in the placebo-controlled pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.

Metformin

Clinical trial data and postmarketing data

Table 3 presents adverse reactions by system organ class and by frequency category. Frequency categories are based on information available from metformin Summary of Product Characteristics available in the European Union.

Table 3. The frequency of metformin adverse reactions identified from clinical trial and postmarketing data:

¹ 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).
² Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite occur most frequently during initiation of therapy and resolve spontaneously in most cases.