UMEÅ UNIVERSITY MEDICAL DISSERTATION New series No 961 From the Division of Clinical Pharmacology Department of Pharmacology and Clinical Neuroscience Umeå University, Umeå, Sweden Spontaneous Reporting of Adverse Drug Reactions Possibilities and Limitations

Background and objectives: Adverse drug reactions (ADRs) constitute a major problem in society and in drug therapy, both as a health care problem and as an economic burden on society. They are a common cause of short-term hospitalization, prolonged hospitalization and death, especially among the elderly. Spontaneous reporting of ADRs remains one the most effective methods for the detection of new and serious drug reactions. The aim of this thesis was to study the degree of under-reporting, reasons and factors behind this, and to test different measures to increase the rate of ADR reporting. However, spontaneous reporting has several weaknesses, the most important of these being under-reporting. In Sweden physicians are legally required to report fatal and serious ADRs. In an international comparison, Sweden has a high degree of reporting of ADRs. However, we know from previous studies that under-reporting is substantial also in Sweden. Attitudes towards reporting of ADRs among physicians in the northern region of Sweden were investigated using a questionnaire, and the effect on the reporting rate when a new group (nurses) received instruction and were encouraged to report ADRs was studied. Using the Swedish ADR database, we were able to calculate the risk of agranulocytosis associated with the use of metamizole by using consumption data from the case records of scrutinized patients and stored prescriptions. The under-reporting rate of selected diagnoses was investigated by scanning the patient case records and by checking whether these cases had been reported to the national data base. The effect on the reporting rate of ADRs was studied in an intervention study in which a small financial inducement was given to those who reported ADRs. Results: The most important factor for not reporting adverse drug reactions among physicians and general practioners in our region was that the reaction was considered to be well known. Lack of time, interest and giving priority to other matters were other important essential factors for not reporting. During a 12-month study period, 18 ADR reports with a total number of 22 ADRs were sent in by the nurses participating on one study to test nurses as reporters of ADRs. In the year prior to the study period only 2 reports were received from these departments. The median time from the onset of the ADR until we received the report was 12 days (range 1 – 120 days), compared to a median time of 28 days from 50 other geriatric departments in Sweden. Agranulocytosis is a serious ADR that may be caused by metamizole. In the period from 1996 to 1999, ten cases of agranulocytosis during treatment with metamizole were reported to national data base. Metamizole was prescribed to 666 (19%) inpatients during the 3-month study period and 112 prescriptions were identified at the participating pharmacies. Thirtyeight per cent of them indicated treatment for more than 15 days. Making certain assumptions, the calculated risk of agranulocytosis was one out of every 31 000 in-patients and one out of every 1400 out-patients. The degree of under-reporting of serious ADRs was studied in five hospitals in northern Sweden. More than 1300 case records were scrutinized and among these we found 107 cases that according to current rules for ADR reporting, should have been reported. However, only fifteen reports regarding these cases were found in the SADRAC database, which indicates an under-reporting rate of 86%. The effect of a small financial stimulation to increase the reporting rate was studied. From the intervention area we received 62 suspected ADRs compared with 50 from the control area. The increase in the number of reports was 59% compared with an unchanged reporting rate from the control area. Conclusion: The physicians in northern Sweden have a relatively good knowledge of the existing rules for ADR reporting, but their attitudes may allow for a considerable rate of under-reporting. However, nurses could play an important role in detecting and reporting suspected ADRs. When they were included in the reporting system there was a substantial increase in the reporting rate. The risk of developing metamizole induced agranulocytosis is considerably increased if metamizole is given to patients for a longer time than recommended. The rate of reported ADRs is very low, also for serious and fatal reactions. A small financial inducement is one, albeit not the best way to obtain an increase in the reporting rate of suspected ADRs.