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Hazards of Drug Therapy: On the Management of Adverse Drug Reactions: From Signal Detection and Evaluation to Risk Minimization
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Spontaneous reporting systems (SRSs) for adverse drug reactions (ADRs) have been developed as a result of the thalidomide disaster, whereby thousands of children world-wide were born with birth defects. The Swedish Adverse Drug Reactions Advisory Committee was established in 1965. Since 1975, reporting has been compulsory for all suspected serious or new ADRs. International collaboration started in 1968 with countries contributing their ADR reports to an international database set up by the World Health Organization.

ADRs represent the negative side of the benefit-to-risk balance that in theory needs to be counteracted by perceived or established positive drug effects. All drugs are subject to preclinical and clinical testing prior to marketing authorization. However, these studies are insufficient to detect rare ADRs, ADRs that occur after long-term administration or with latency, ADRs that occur in special patient groups such as children, the elderly, patients with renal or hepatic insufficiency or patients on concomitant drug treatment, and ADRs that represent a modest increase in the risk of diseases (including mortality) that are prevalent in the study population. Postmarketing surveillance of drugs is therefore essential, and regulatory action may be needed on the basis of new ADR information.

SRSs are important sources of ADR information as exemplified here by the evaluation of peripheral sensory disturbances with fluoroquinolones, hyponatremia with antidepressants, blood dyscrasias with dipyrone, glucose intolerance with atypical antipsychotics, pulmonary embolism with combined oral contraceptives and extrapyramidal symptoms with selective serotonin reuptake inhibitors. SRSs can be used to study clinical manifestations of ADRs (that can give insights into potential ADR mechanisms), risk factors for the ADR or for specific outcomes of the ADR, and ADR reporting incidences when combined with sales data. Signals from SRSs may need to be studied further e.g., by use of large-scale epidemiologic studies based on record linkage between drug prescription databases and health databases. Owing to the rapid availability of information, however, SRSs are likely to remain of major importance for the post-marketing surveillance of drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 54
Keywords [en]
Pharmacology, adverse drug reactions, spontaneous reporting systems, drug regulation, pharmacovigilance, incidence
Keywords [sv]
Farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-5866ISBN: 91-554-6291-X (print)OAI: oai:DiVA.org:uu-5866DiVA, id: diva2:166671
Public defence
2005-09-16, Enghoffsalen, Ingång 50, Akademiska sjukhuset, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Peripheral sensory disturbances related to treatment with fluoroquinolones
Open this publication in new window or tab >>Peripheral sensory disturbances related to treatment with fluoroquinolones
1996 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 37, no 4, p. 831-837Article in journal (Refereed) Published
Abstract [en]

The symptoms and possible risk factors of peripheral sensory disturbances related to fluoroquinolones are reviewed on the basis of 37 reports submitted to the Swedish Adverse Drug Reactions Advisory Committee. In 25 patients (68%), symptoms occurred within 1 week after start of treatment. Paraesthesia was the most common complaint and occurred in 81% of the cases. Fifty-one per cent of the reports concerned numbness/hypoaesthesia, 27% pain/hyperaesthesia and 11% muscle weakness. Seventy-one per cent of the patients recovered within 2 weeks after drug discontinuation. Possible predisposing factors were impaired renal function, diabetes, lymphatic malignancy and treatment with another drug known to cause neuropathy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93240 (URN)8722551 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
2. Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organization data base for spontaneous reporting of adverse drug reactions
Open this publication in new window or tab >>Hyponatremia in relation to treatment with antidepressants: a survey of reports in the World Health Organization data base for spontaneous reporting of adverse drug reactions
1997 (English)In: Pharmacotherapy, ISSN 0277-0008, E-ISSN 1875-9114, Vol. 17, no 2, p. 348-352Article in journal (Refereed) Published
Abstract [en]

To determine the risk factors associated with the development of hyponatremia during treatment with antidepressant drugs, we conducted a retrospective register study of the World Health Organization (WHO) data base for spontaneous reporting of adverse drug reactions. From the start of the WHO Collaborating Centre for International Drug Monitoring in 1968 until the end of 1993, 668 reports of antidepressant-associated hyponatremia disorders were submitted. Seventy-eight percent of them concerned women, compared with 69% for all other adverse drug reactions with antidepressants (p < 0.0005). The mean age of all patients was 66.6 years, compared with 48.6 years for the other adverse drug reactions (p < 0.0001). In 51.3% of the patients the reaction occurred within the first 2 weeks of treatment. Significantly more cases occurred during the summer than during the other seasons (p < 0.02). The risk for hyponatremia during treatment with antidepressants seems to be highest in women, in the elderly, during the summer, and during the first weeks of treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93241 (URN)9085327 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
3. Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole)
Open this publication in new window or tab >>Agranulocytosis and other blood dyscrasias associated with dipyrone (metamizole)
2002 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 58, no 4, p. 265-274Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Agranulocytosis is a potentially lethal adverse drug reaction of dipyrone (metamizole). According to case-control studies, the frequency is low, approximately one per million users. The aim of the study was to describe the pattern of blood dyscrasias associated with dipyrone, identify possible risk factors and calculate the incidence of agranulocytosis associated with dipyrone. METHODS: All spontaneous reports of serious blood dyscrasias associated with dipyrone in Sweden were reviewed. The reports were scrutinised for additional information, including bone marrow findings. The reported incidence of agranulocytosis was estimated from total prescription sales of dipyrone. RESULTS: The reported incidence of agranulocytosis with dipyrone in Sweden was estimated to be at least 1:1439 (95% confidence interval 1:850, 1:4684) prescriptions. Ninety-two percent of the cases of blood dyscrasias occurred during the first 2 months of treatment. Additional risk factors were identified in 36% of the patients. In a total of five cases of which four were fatal, all three haematopoieses were affected according to bone marrow sample findings. Among the fatal cases, a higher proportion had bi- or tricytopenia than among the non-fatal cases ( P<0.005). CONCLUSION: Based on sales data and spontaneous reporting of adverse drug reactions in Sweden, the risk of agranulocytosis with dipyrone seems to be considerably higher than the previously estimated risks. Dipyrone is also associated with other blood dyscrasias, and the prognosis for combined dyscrasias seems to be poorer than for isolated agranulocytosis.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93242 (URN)10.1007/s00228-002-0465-2 (DOI)12136373 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
4. Glucose intolerance with atypical antipsychotics
Open this publication in new window or tab >>Glucose intolerance with atypical antipsychotics
Show others...
2002 (English)In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 25, no 15, p. 1107-1116Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Previous studies have suggested that the atypical antipsychotics clozapine and olanzapine may be associated with an increased risk of glucose intolerance and diabetes mellitus. Early studies have also suggested an association between use of conventional antipsychotics and the development of glucose intolerance. OBJECTIVE: To examine quantitatively the association between glucose intolerance including diabetes mellitus and the use of the atypical antipsychotics clozapine, olanzapine or risperidone, and to identify possible risk factors for the development of glucose intolerance during treatment with these drugs. METHODS: All reports suggestive of glucose intolerance for clozapine, olanzapine and risperidone were identified in the WHO database for adverse drug reactions. In the analyses of possible risk factors for glucose intolerance all other reports of adverse drug reactions for clozapine, olanzapine and risperidone were used as reference. Using the Bayesian Confidence Propagation Neural Network method, the strengths of the associations over time between glucose intolerance and the use of these drugs were analysed. For comparison, the strengths of the associations between glucose intolerance and the use of the conventional antipsychotics haloperidol and chlorpromazine were also analysed. RESULTS: Clozapine, olanzapine and risperidone were significantly associated with glucose intolerance. In contrast, chlorpromazine and haloperidol were not associated with glucose intolerance. For clozapine, olanzapine and risperidone grouped together, the following potential risk factors for glucose intolerance were identified: an underlying diabetic condition (odds ratio [OR] 10.22, 95% CI 8.20-12.73), an increase in weight (OR 2.36, 95% CI 1.76-3.17), male gender (OR 1.27, 95% CI 1.11-1.47), and concomitant use of valproic acid (OR 1.97, 95% CI 1.61-2.40), selective serotonin reuptake inhibitors (OR 1.63, 95% CI 1.33-1.99) or buspirone (OR 2.24, 95% CI 1.33-3.77). CONCLUSION: Treatment with clozapine, olanzapine or risperidone appears to be associated with an increased risk of glucose intolerance.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93243 (URN)12452735 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
5. Pulmonary embolism associated with combined oral contraceptives: reporting incidences and potential risk factors for a fatal outcome
Open this publication in new window or tab >>Pulmonary embolism associated with combined oral contraceptives: reporting incidences and potential risk factors for a fatal outcome
2004 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 83, no 6, p. 576-585Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: It is established that combined oral contraceptive (COC) treatment increases the risk of a pulmonary embolism (PE), but specific risk factors for a fatal outcome from a PE remain to be determined. This study aimed to identify such risk factors, and to calculate the reporting rates of fatal and non-fatal PE. METHODS: Cases of suspected PE during treatment with COCs reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) between 1965 and 2001 were included. Medical records were scrutinized for potential risk factors for a venous thromboembolism (VTE). Annual sales data were obtained from the National Corporation of Pharmacies. RESULTS: A total of 248 cases of a suspected PE were reported; 207 non-fatal and 41 fatal. A VTE was verified in all fatal, and in 83.5% of non-fatal cases. The presence of nausea or abdominal pain, an age >35 years, concomitant treatment with other drugs which may increase the VTE risk, vein or lymph vessel malformation, and a deep vein thrombosis above the knee level were positively associated with a fatal outcome. Chest pain and previous COC use were negatively associated with a fatal outcome. The reporting rate of a PE with a verified VTE was 1.72 (95% confidence interval 1.47-2.00) cases per 100 000 treatment years, and of a fatal PE 0.25 (95% confidence interval 0.16-0.37) cases per 100 000 treatment years. CONCLUSION: Several specific potential risk factors for a fatal outcome from a COC-induced PE were identified. Recognition of these in combination with a high suspicion of VTE in COC users may reduce the risk of a fatal outcome.

Keywords
combined oral contraceptives, pulmonary embolism, risk factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-93244 (URN)10.1111/j.0001-6349.2004.0533.x (DOI)15144341 (PubMedID)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2017-12-14Bibliographically approved
6. Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme and serotonin and dopamine transporter and receptor mutations
Open this publication in new window or tab >>Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme and serotonin and dopamine transporter and receptor mutations
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-93245 (URN)
Available from: 2005-06-02 Created: 2005-06-02 Last updated: 2010-01-13Bibliographically approved

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