Monitoring the safety of pioglitazone : results of a prescription-event monitoring study of 12,772 patients in England.

Background: Pioglitazone is an antidiabetic drug that targets insulin resistance in patients with type 2 diabetes mellitus by stimulating the peroxisome proliferator-activated receptor (PPAR)-gamma. Pioglitazone belongs to a class of drugs called thiazolidinediones (TZDs) and was launched in the UK in November 2000.

Objective: To monitor, using prescription-event monitoring, the post-marketing safety of pioglitazone, which is prescribed in primary care in England.

Methods: An observational cohort study in which patients were identified from dispensed prescriptions issued by primary-care physicians/general practitioners (GPs) between November 2000 and June 2001. Information on demographics, the use of pioglitazone, clinical event data, events suspected as adverse drug reactions, reasons for stopping the drug and cause of death (if appropriate) were collected using questionnaires posted to GPs at least 8 months after the date of first prescription for each patient. Event incidence densities (IDs) [number of first reports of an event/1000 patient-months of exposure] were calculated.

Results: The cohort comprised 12 772 patients (median age 62 years); 53.1% were males. The most frequent starting daily dose of pioglitazone was either 15 mg or 30 mg (n = 10 298). Pioglitazone/metformin was the most frequently used combination reported (n = 4029). Of the 3690 patients who stopped treatment, 1143 stopped due to reasons related to poor glycaemic control. 'Oedema/fluid retention' (n = 121) and 'weight gain' (n = 118) also appeared high on the list of reasons for discontinuing. 'Malaise/lassitude' and 'nausea/vomiting' were the most frequently reported suspected adverse drug reactions (ADRs) associated with pioglitazone. Specific clinical events considered as early onset events with pioglitazone were: 'malaise/lassitude', 'nausea/vomiting', 'dizziness', 'headache/migraine', 'diarrhoea', 'weight gain' and 'abnormal liver function test'.

Conclusion: Pioglitazone was considered to be a reasonably well tolerated drug, with the main reasons for discontinuing being related to the drug not being effective. The frequency of individual ADRs reported in this study did not exceed the frequency in the summary of product characteristics (SPC) for pioglitazone. However, amongst the frequently reported suspected ADRs, 'nausea/vomiting' and 'diarrhoea' are not listed in the SPC. Further research is required to assess whether the risk of myocardial infarction and deaths due to cardiovascular causes is a class effect of the thiazolidinediones. Results from this study should be taken into account with other clinical and pharmacoepidemiological studies.