In the 24-week active-controlled monotherapy trial, serious adverse events were reported in 3.6% (19/528) of the GLUMETZA-treated patients compared to 2.9% (5/174) of the patients treated with immediate-release metformin. During the 6-month open-label, uncontrolled, extension trial, an additional 10 (4.0%) GLUMETZA-treated patients reported a serious adverse event In the add-on to sulfonylurea study, a serious adverse event was reported in 2.1% (9/431) of the GLUMETZA+glyburide treated patients compared to 1.4% (2/144) of the placebo+glyburide treated patients. When the data from all clinical trials were combined, the most frequently (incidence ≥0.5 %) reported serious adverse events classified by system organ class were gastrointestinal disorders (1.0% of GLUMETZA-treated patients compared to 0% of patients not treated with GLUMETZA) and cardiac disorders (0.4% of GLUMETZA-treated patients compared to 0.5% of patients not treated with GLUMETZA). Only 2 serious adverse events (unstable angina [n=2] and pancreatitis [n=2]) were reported in more than one GLUMETZA-treated patient.

In the placebo-controlled study, patients receiving background glyburide (SU; sulfonylurea) therapy were randomized to receive add-on treatment of either one of three different regimens of GLUMETZA or placebo. In total, 431 patients received GLUMETZA + SU and 144 patients placebo + SU. Adverse events reported in greater than 5% of patients treated with GLUMETZA that were more common in the combined GLUMETZA + SU group than in the placebo + SU group are shown in Table 5.

In 0.7% of patients treated with GLUMETZA + SU, diarrhea was responsible for discontinuation of study medication compared to zero in the placebo + SU group.

In the same study, the following adverse events were reported by 1-5% of patients for the combined Glumetza + SU group and these events occurred more commonly in the Glumetza-treated than in the placebo-treated patients:

Ear and labyrinth disorders: ear pain

Gastrointestinal disorders: vomiting NOS, dyspepsia, flatulence, abdominal pain upper, abdominal distension, abdominal pain NOS, toothache, loose stools

General disorders and administration site conditions: asthenia, chest pain

Immune system disorders: seasonal allergy

Infections and infestations: gastroenteritis viral NOS, tooth abscess, tonsillitis, fungal infection NOS

Injury, poisoning and procedural complications: muscle strain

Musculoskeletal and connective tissue disorders: pain in limb, myalgia, muscle cramp

Nervous system disorders: dizziness, tremor, sinus headache, hypoaesthesia

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: contusion

Vascular disorders: hypertension NOS

No cases of overdose were reported during GLUMETZA clinical trials. It would be expected that adverse reactions of a more intense character including epigastric discomfort, nausea, and vomiting followed by diarrhea, drowsiness, weakness, dizziness, malaise and headache might be seen. Should those symptoms persist, lactic acidosis should be excluded. The drug should be discontinued and proper supportive therapy instituted. In other metformin clinical trials, hypoglycemia has not been seen even with ingestion of up to 85 grams of metformin, although lactic acidosis has occurred in such circumstances (see  WARNINGS ). Metformin i