Evidence: safety

Advice

The metformin summary of product characteristics notes that during initiation of treatment with metformin the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These resolve spontaneously in most people.

In the 3 RCTs included in the Cochrane review that compared metformin monotherapy with co-cyprindiol (Morin-Papunen et al. 2000, Harborne et al. 2003 and Morin-Papunen et al. 2003), metformin caused a significantly higher incidence of severe gastrointestinal adverse effects that resulted in medication being stopped (Peto OR 7.75, p=0.02, 95% CI 1.32 to 45.71) and a significantly lower incidence of other severe adverse events that resulted in medication being stopped (weight gain, high blood pressure, depression, chest pain and headache; Peto OR 0.11, p=0.0008, 95% CI 0.03 to 0.39).

The RCT comparing metformin plus Cilest (oral contraceptive containing ethinylestradiol 35 micrograms plus norgestimate 250 micrograms) with Cilest monotherapy (Cibula et al. 2005) found no difference between the treatments in the rate of severe gastrointestinal adverse effects that resulted in medication being stopped (p=0.49). The RCT comparing metformin plus co-cyprindiol with co-cyprindiol (Elter et al. 2002) reported minor adverse effects and no difference was seen between the groups (p=0.11).

Cetinkalp et al. (2009) did not report details of adverse effects. Luque-Ramirez et al. (2007) reported mild to moderate gastrointestinal adverse effects in 2 out of 19 women receiving metformin, who stopped treatment. No adverse effects were reported for women receiving co-cyprindiol. Meyer et al. (2007) reported that 1 woman in the co-cyprindiol group and 1 woman in the ethinylestradiol/levonorgestrel/spironolactone group stopped treatment because of mood swings; adverse effects were not reported in the metformin group. Wu et al. (2008) reported mild to moderate gastrointestinal problems with metformin monotherapy that affected 2 of 20 women (these women did not need to stop treatment); however, moderate gastrointestinal problems in 4 out of 20 women receiving metformin plus co-cyprindiol led them to leave the study.