Metformin and Dapagliflozin

A GFR should be assessed before initiation of treatment with metformin containing medicinal 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 metformin in patients with GFR <60 mL/min.

If no adequate strength of dapagliflozin/metformin is available, individual mono-components should be used instead of the fixed dose combination.

Dosage in patients with renal impairment:

There are no data from the use of dapagliflozin/metformin or dapagliflozin in pregnant women. Studies in rats treated with dapagliflozin have shown toxicity to the developing kidney in the time period corresponding to the second and third trimesters of human pregnancy. Therefore, the use of this medicinal product is not recommended during the second and third trimesters of pregnancy. A limited amount of data from the use of metformin in pregnant women does not indicate 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.

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.

It is unknown whether this medicinal product or dapagliflozin (and/or its metabolites) are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of dapagliflozin/metabolites in milk, as well as pharmacologically-mediated effects in nursing offspring. Metformin is excreted in human milk in small amounts. A risk to the newborns/infants cannot be excluded.

This medicinal product should not be used while breast-feeding.

Fertility

The effect of this medicinal product or dapagliflozin on fertility in humans has not been studied. In male and female rats, dapagliflozin showed no effects on fertility at any dose tested. For metformin, studies in animals have not shown reproductive toxicity.

Dapagliflozin/metformin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when this medicinal product is used in combination with other glucose-lowering medicinal products known to cause hypoglycaemia.

Dapagliflozin/metformin fixed combination has been demonstrated to be bioequivalent with coadministered dapagliflozin and metformin. There have been no therapeutic clinical trials conducted with dapagliflozin/metformin tablets.

Dapagliflozin plus metformin

Summary of the safety profile

In an analysis of 5 placebo-controlled dapagliflozin add-on to metformin studies, the safety results were similar to that of the pre-specified pooled analysis of 13 placebo-controlled dapagliflozin studies (see Dapagliflozin, Summary of the safety profile below). No additional adverse reactions were identified for the dapagliflozin plus metformin group compared with those reported for the individual components. In the separate dapagliflozin add-on to metformin pooled analysis, 623 subjects were treated with dapagliflozin 10 mg as add-on to metformin and 523 were treated with placebo plus metformin.

Dapagliflozin

Summary of the safety profile

In the clinical studies in type 2 diabetes, more than 15,000 patients have been treated with dapagliflozin.

The primary assessment of safety and tolerability was conducted in a pre-specified pooled analysis of 13 short-term (up to 24 weeks) placebo-controlled studies with 2,360 subjects treated with dapagliflozin 10 mg and 2,295 treated with placebo.

In the dapagliflozin cardiovascular outcomes study (DECLARE), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.

The most frequently reported adverse reactions across the clinical studies were genital infections.

Tabulated list of adverse reactions

The following adverse reactions have been identified in the placebo-controlled dapagliflozin plus metformin clinical studies, dapagliflozin clinical studies and metformin clinical studies and post-marketing experience. None were found to be dose-related. Adverse reactions listed below are classified according to frequency and system organ class. Frequency categories are defined according to the following convention: 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), and not known (cannot be estimated from the available data).

Adverse reactions in dapagliflozin and metformin immediate-release clinical trial and post-marketing data^a:

^a The table shows adverse reactions identified from up to 24-week (short-term) data regardless of glycaemic rescue, except those marked with §, for which adverse reaction and frequency categories are based on information from the metformin Summary of Product Characteristics available in the European Union.
^b See corresponding subsection below for additional information.
^c Vulvovaginitis, balanitis and related genital infections includes, e.g. the predefined preferred terms: vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial, vulval abscess.
^d Urinary tract infection includes the following preferred terms, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection and prostatitis.
^e Volume depletion includes, e.g. the predefined preferred terms: dehydration, hypovolaemia, hypotension.
^f Polyuria includes the preferred terms: pollakiuria, polyuria, urine output increased.
^g Mean changes from baseline in haematocrit were 2.30% for dapagliflozin 10 mg versus -0.33% for placebo. Haematocrit values >55% were reported in 1.3% of the subjects treated with dapagliflozin 10 mg versus 0.4% of placebo subjects.
^h 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).
ⁱ 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.
^j Mean percent change from baseline for dapagliflozin 10 mg versus placebo, respectively, was: total cholesterol 2.5% versus 0.0%; HDL cholesterol 6.0% versus 2.7%; LDL cholesterol 2.9% versus -1.0%; triglycerides -2.7% versus -0.7%.
^l Reported in the cardiovascular outcomes study in patients with type 2 diabetes (DECLARE). Frequency is based on annual rate.
^m Adverse reaction was identified through post-marketing surveillance with the use of dapagliflozin. Rash includes the following preferred terms, listed in order of frequency in clinical trials: rash, rash generalised, rash pruritic, rash macular, rash maculo-papular, rash pustular, rash vesicular, and rash erythematous. In active- and placebo-controlled clinical trials (dapagliflozin, N=5936, All control, N=3403), the frequency of rash was similar for dapagliflozin (1.4%) and all control (1.4%), respectively.
^* Reported in ≥2% of subjects and ≥ 1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.
^** Reported by the investigator as possibly related, probably related or related to study treatment and reported in ≥0.2% of subjects and ≥0.1% more and at least 3 more subjects treated with dapagliflozin 10 mg compared to placebo.

Description of selected adverse reactions

Dapagliflozin plus metformin

Hypoglycaemia

In studies with dapagliflozin in add-on combination with metformin, minor episodes of hypoglycaemia were reported at similar frequencies in the group treated with dapagliflozin 10 mg plus metformin (6.9%) and in the placebo plus metformin group (5.5%). No major events of hypoglycaemia were reported. Similar observations were made for the combination of dapagliflozin with metformin in drug-naive patients.

In an add-on to metformin and a sulphonylurea study, up to 24 weeks, minor episodes of hypoglycaemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and a sulphonylurea and in 3.7% of subjects who received placebo plus metformin and a sulphonylurea. No major events of hypoglycaemia were reported.

Dapagliflozin

Vulvovaginitis, balanitis and related genital infections

In the 13-study safety pool, vulvovaginitis, balanitis and related genital infections were reported in 5.5% and 0.6% of subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females (8.4% and 1.2% for dapagliflozin and placebo, respectively), and subjects with a prior history were more likely to have a recurrent infection.

In the dapagliflozin cardiovascular outcomes study, the number of patients with serious adverse events of genital infections were few and balanced: 2 patients in each of the dapagliflozin and placebo groups.

Necrotising fasciitis of the perineum (Fournier’s gangrene)

Cases of Fournier’s gangrene have been reported postmarketing in patients taking SGLT2 inhibitors, including dapagliflozin.

In the DECLARE study with 17,160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier’s gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.

Hypoglycaemia

The frequency of hypoglycaemia depended on the type of background therapy used in each study.

For studies of dapagliflozin as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (<5%) between treatment groups, including placebo up to 102 weeks of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with dapagliflozin or placebo. In a study with add-on insulin therapy, higher rates of hypoglycaemia were observed.

In an add-on to insulin study up to 104 weeks, episodes of major hypoglycaemia were reported in 0.5% and 1.0% of subjects in dapagliflozin 10 mg plus insulin at Weeks 24 and 104, respectively, and in 0.5% of subjects treated with placebo plus insulin groups at Weeks 24 and 104. At Weeks 24 and 104, minor episodes of hypoglycaemia were reported, respectively, in 40.3% and 53.1% of subjects who received dapagliflozin 10 mg plus insulin and in 34.0% and 41.6% of the subjects who received placebo plus insulin.

In the DECLARE study, no increased risk of major hypoglycaemia was observed with dapagliflozin therapy compared with placebo. Major events of hypoglycaemia were reported in 58 (0.7%) patients treated with dapagliflozin and 83 (1.0%) patients treated with placebo.

Volume depletion

In the 13-study safety pool, reactions suggestive of volume depletion (including, reports of dehydration, hypovolaemia or hypotension) were reported in 1.1% and 0.7% of subjects who received dapagliflozin 10 mg and placebo, respectively; serious reactions occurred in <0.2% of subjects balanced between dapagliflozin 10 mg and placebo.

In the DECLARE study, the numbers of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and ACE-I/ARB use. In patients with eGFR <60 mL/min/1.73 m² at baseline, there were 19 events of serious adverse events suggestive of volume depletion in the dapagliflozin group and 13 events in the placebo group.

Diabetic ketoacidosis

In the DECLARE study, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population.

Urinary tract infections

In the 13-study safety pool, urinary tract infections were more frequently reported for dapagliflozin compared with placebo (4.7% versus 3.5%, respectively). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection.

In the DECLARE study, serious events of urinary tract infections were reported less frequently for dapagliflozin 10 mg compared with placebo, 79 (0.9%) events versus 109 (1.3%) events, respectively.

Increased creatinine

Adverse reactions related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). This grouping of reactions was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥60 mL/min/1.73 m²) this grouping of reactions were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These reactions were more common in patients with baseline eGFR ≥30 and <60 mL/min/1.73 m² (18.5% dapagliflozin 10 mg versus 9.3% placebo).

Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤0.5 mg/dL from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.

In the DECLARE study, including elderly patients and patients with renal impairment (eGFR less than 60 mL/min/1.73 m²), eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared with the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.