Metformin and Empagliflozin

The glycaemic efficacy of empagliflozin is dependent on renal function.

A eGFR 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.

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

Posology for renally mild impaired patients:

The glycaemic efficacy of empagliflozin is dependent on renal function. For cardiovascular risk reduction as add on to standard of care, a dose of 10 mg empagliflozin daily should be used in patients with an eGFR below 60 ml/min/1.73 m². Because the glycaemic lowering efficacy of empagliflozin is reduced in patients with moderate renal impairment and likely absent in patients with severe renal impairment, if further glycaemic control is needed, the addition of other antihyperglycaemic agents should be considered.

A eGFR 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.

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

Posology for renally moderate impaired patients^a:

^a patients with type 2 diabetes mellitus and established cardiovascular disease

There are no data from the use of this medicinal product or empagliflozin in pregnant women. Animal studies show that empagliflozin crosses the placenta during late gestation to a very limited extent but do not indicate direct or indirect harmful effects with respect to early embryonic development. However, animal studies have shown adverse effects on postnatal development. 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 the combination of empagliflozin and metformin or with metformin alone have shown reproductive toxicity at higher doses of metformin only.

When the patient plans to become pregnant, and during pregnancy, it is recommended that diabetes is not treated with this medicinal product, but insulin be used to maintain blood glucose levels as close to normal as possible, to reduce the risk of malformations of the foetus associated with abnormal blood glucose levels.

Metformin is excreted into human milk. No effects have been shown in breastfed newborns/infants of treated women. No data in humans are available on excretion of empagliflozin into milk. Available animal data have shown excretion of empagliflozin and metformin in milk. A risk to the newborns/infants cannot be excluded.

This medicinal product should not be used during breast feeding.

Fertility

No studies on the effect on human fertility have been conducted for this medicinal product or empagliflozin. Animal studies with empagliflozin and metformin do not indicate direct or indirect harmful effects with respect to fertility.

Empagliflozin/metformin has minor influence on the ability to drive and use machines. Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines, in particular when empagliflozin/metformin is used in combination with a sulphonylurea and/or insulin.

Summary of the safety profile

The most commonly reported adverse reactions in clinical trials were hypoglycaemia in combination with insulin and/or sulphonylurea and gastrointestinal symptoms (nausea, vomiting, diarrhoea, abdominal pain and loss of appetite). No additional adverse reactions were identified in clinical trials with empagliflozin as add-on to metformin compared to the side effects of the single components.

Tabulated list of adverse reactions

The adverse reactions are listed by 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).

Tabulated list of adverse reactions (MedDRA) from placebo-controlled studies and from post-marketing experience:

¹ See subsections below for additional information
² Identified adverse reactions of empagliflozin monotherapy
³ Identified adverse reactions of metformin monotherapy
⁴ 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.
^a Mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 5.0% and 5.2% versus 3.7%; HDL-cholesterol 4.6% and 2.7% versus -0.5%; LDL-cholesterol 9.1% and 8.7% versus 7.8%; triglycerides 5.4% and 10.8% versus 12.1%.
^b Mean changes from baseline in haematocrit were 3.6% and 4.0% for empagliflozin 10 mg and 25 mg, respectively, compared to 0% for placebo. In the EMPA-REG Outcome study, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
^c Pooled data of empagliflozin trials in patients with heart failure (where half of the patients had type 2 diabetes mellitus) showed a higher frequency of volume depletion (“very common”: 11.4% for empagliflozin versus 9.7% for placebo).

Description of selected adverse reactions

Hypoglycaemia

The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as add-on to metformin, as add-on to linagliptin and metformin, for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components, and as adjunct to standard care therapy. An increased frequency was noted when empagliflozin given as add-on to metformin and a sulfonylurea (empagliflozin 10 mg: 16.1%, empagliflozin 25 mg: 11.5% and placebo: 8.4%), or as add-on to metformin and insulin (empagliflozin 10 mg: 31.3%, empagliflozin 25 mg: 36.2% and placebo: 34.7%).

Major hypoglycaemia (events requiring assistance)

The overall frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo as add-on to metformin, and for the combination of empagliflozin with metformin in drug-naïve patients compared to those treated with empagliflozin and metformin as individual components, and as adjunct to standard care therapy. Major hypoglycaemic events occurred in 0.5%, 0% and 0.5% of patients treated with empagliflozin 10 mg, empagliflozin 25 mg and placebo when added on to metformin and insulin, respectively. No patient had a major hypoglycaemic event in the combination with metformin and a sulphonylurea and as add-on to linagliptin and metformin.

Urinary tract infection

The overall frequency of urinary tract infection adverse events was higher in metformin-treated patients who received empagliflozin 10 mg (8.8%) compared to empagliflozin 25 mg (6.6%) or placebo (7.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections (i.e. mild/moderate/severe) was similar to placebo. Urinary tract infection events were reported more frequently for empagliflozin 10 mg compared with placebo in female patients, but not for empagliflozin 25 mg. The frequencies of urinary tract infections were low for male patients and were balanced across treatment groups.

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection

Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently in metformin-treated patients who received empagliflozin 10 mg (4.0%) and empagliflozin 25 mg (3.9%) compared to placebo (1.3%), and were reported more frequently for empagliflozin compared to placebo in female patients. The difference in frequency was less pronounced in male patients. Genital tract infections were mild and moderate in intensity, none was severe in intensity.

Increased urination

As expected from the mechanism of action, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in metformin-treated patients who received empagliflozin 10 mg (3.0%) and empagliflozin 25 mg (2.9%) compared to placebo (1.4%) as add-on to metformin therapy. Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin (<1%).

Volume depletion

The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) in metformin-treated patients who received empagliflozin was low: 0.6% for empagliflozin 10 mg, 0.3% for empagliflozin 25 mg and 0.1% for placebo. The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older. In patients ≥75 years of age volume depletion events have been reported in a single patient treated with empagliflozin 25 mg as add-on to metformin therapy.

Blood creatinine increased/Glomerular filtration rate decreased

The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate were similar between empagliflozin and placebo as add-on to metformin (blood creatinine increased: empagliflozin 10 mg 0.5%, empagliflozin 25 mg 0.1%, placebo 0.4%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.2%). Initial increases in creatinine and initial decreases in estimated glomerular filtration rates in patients treated with empagliflozin as add-on to metformin therapy were generally transient during continuous treatment or reversible after drug discontinuation of treatment. Consistently, in the EMPA-REG OUTCOME study, patients treated with empagliflozin experienced an initial fall in eGFR (mean: 3 ml/min/1.73 m²). Thereafter, eGFR was maintained during continued treatment. Mean eGFR returned to baseline after treatment discontinuation suggesting acute haemodynamic changes may play a role in these renal function changes.