An evaluation of computer-aided disproportionality analysis for post-marketing signal detection.

To understand the value of computer-aided disproportionality analysis (DA) in relation to current pharmacovigilance signal detection methods, four products were retrospectively evaluated by applying an empirical Bayes method to Merck's post-marketing safety database. Findings were compared with the prior detection of labeled post-marketing adverse events. Disproportionality ratios (empirical Bayes geometric mean lower 95% bounds for the posterior distribution (EBGM05)) were generated for product-event pairs. Overall (1993-2004 data, EBGM05> or =2, individual terms) results of signal detection using DA compared to standard methods were sensitivity, 31.1%; specificity, 95.3%; and positive predictive value, 19.9%. Using groupings of synonymous labeled terms, sensitivity improved (40.9%). More of the adverse events detected by both methods were detected earlier using DA and grouped (versus individual) terms. With 1939-2004 data, diagnostic properties were similar to those from 1993 to 2004. DA methods using Merck's safety database demonstrate sufficient sensitivity and specificity to be considered for use as an adjunct to conventional signal detection methods.

Identification of sulfonamide-like adverse drug reactions to celecoxib in the World Health Organization database.

BACKGROUND: The selective COX-2 inhibitor celecoxib has a sulfonamide structure and is contraindicated for patients with known sulfa allergy. However, there is currently no standard available for the identification of sulfonamide-related adverse drug reactions (ADRs) and the occurrence of such ADRs with celecoxib has not been established. THE AIMS OF THIS STUDY WERE: (1) to identify the typical pattern of sulfonamide ADRs from literature and verify this pattern in the World Health Organization (WHO) ADR database; and (2) to examine whether these sulfonamide ADRs occur more frequently with celecoxib than with the non-sulfonamide, COX-2 inhibitor rofecoxib. METHODS: A sulfonamide ADR pattern was derived from the most extensive textbook source of ADRs and applied to the WHO database for the three groups of sulfonamide drugs: short- and intermediate-acting sulfonamides, and sulfasalazine. ADRs reported three or more times for each of these groups were included in a 'sulfonamide template' comprising 19 ADRs relating to the skin, the blood, the liver, and anaphylaxis. This template was then applied to celecoxib and rofecoxib. RESULTS: Overall, the relative reporting rate of a sulfonamide-type ADR with celecoxib was 80% higher than with rofecoxib, whether this was based on total number of reports (RR 1.8, 95% Cl 1.6-1.9) or restricted to reports that listed coxibs as the sole suspected drugs (RR 1.8, 95% Cl 1.6-1.9). There were numerically more ADRs for celecoxib than for rofecoxib in 15 of the 19 terms. Within the ADRs in the sulfonamide template, relative reporting rate of fatal reactions was 80% higher with celecoxib (RR 1.8, 95% Cl 0.9-4.0). Even though serious sulfonamide reactions are rare, their clinical impact on patient safety warrants close monitoring as more data becomes available. Physicians should be aware of possible sulfonamide allergy when prescribing celecoxib.

Polymorphisms of NAT2 in relation to sulphasalazine-induced agranulocytosis.

Agranulocytosis is a rare, but serious adverse reaction to sulphasalazine. The polymorphic enzyme N-acetyltransferase 2 (NAT2) plays an important role in the metabolism of sulphasalazine. This study was conducted to analyse whether the risk of sulphasalazine-induced agranulocytosis is increased in slow acetylators. Patients were treated for inflammatory disease, mostly joint disease, with a mean dose of 2 g sulphasalazine daily. Thirty-nine patients reacted with agranulocytosis, while 75 patients had been treated for a minimum of 3 months without haematological side-effects. A population-based control panel of 448 individuals was used for comparison. All subjects were genotyped for NAT2 by polymerase chain reaction followed by restriction enzyme digestion. The six most common allelic variants were analysed: NAT2*4, NAT2*5A, NAT2*5B, NAT2*5C, NAT2*6 and NAT2*7. The proportion of slow acetylators was significantly higher in patients with sulphasalazine-induced agranulocytosis (69%) and population-based controls (64%) compared to patients who tolerated sulphasalazine (45%); odds ratio 2.71 [95% confidence interval (CI) 1.20; 6.15], P = 0.015, and odds ratio 2.17 (95% CI 1.32; 3.56), P = 0.002, respectively. Patients who developed agranulocytosis did not differ from population-based control subjects in the frequency of slow acetylators; odds ratio 1.25 (95% CI 0.62; 2.53), P = 0.535. The risk of agranulocytosis did not appear to be increased in slow acetylators, provided that the difference compared with sulphasalazine-treated control subjects was not due to a predominance of fast acetylators among patients with inflammatory joint disease. Instead, selection bias was suspected since more slow acetylators may have discontinued sulphasalazine therapy because of drug-intolerance.

The risk of acute major upper gastrointestinal bleeding among users of aspirin and ibuprofen at various levels of alcohol consumption.

OBJECTIVE: Major upper gastrointestinal bleeding (UGIB) is the most important adverse effect of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Alcoholic beverages also precipitate UGIB. This analysis was conducted to evaluate whether the deleterious effects of NSAIDs are further increased among drinkers. METHODS: An interview-based, case-control study was conducted in the U.S. and Sweden; 1224 patients hospitalized with acute major UGIB due to newly occurring peptic ulcer or gastritis were compared to 2945 neighbor controls. RESULTS: Compared with those who drank less than one drink/wk, the relative risk of acute UGIB increased with increasing alcohol consumption, rising to 2.8 among those who drank > or = 21 drinks/wk. Among current drinkers, the relative risk of acute UGIB due to the use of aspirin was raised at all levels of alcohol consumption; the estimate for aspirin taken at least every other day (regular use) at doses of > 325 mg among all current drinkers combined was 7.0; for regular use at lower doses, the corresponding estimate was 2.8, and for any occasional use, it was 2.4. All estimates were statistically significant. Data for ibuprofen were more limited, but the relative risk estimates did not appear to vary consistently with level of alcohol consumption. For regular use (all doses combined), the estimate among all drinkers combined was significantly elevated, at 2.7; occasional ibuprofen use was not associated with UGIB (1.2). There were insufficient data to evaluate other NSAIDs according to alcohol consumption. CONCLUSIONS: The findings suggest that acute UGIB is similarly associated with the use of the two most common nonprescription NSAIDs, aspirin and ibuprofen, at all levels of alcohol consumption. As heavy alcohol intake independently increases the risk, the incidence of UGIB is highest among persons who are both heavy drinkers and users of aspirin or ibuprofen.

Clinical aspects of upper gastrointestinal bleeding associated with the use of nonsteroidal antiinflammatory drugs.

OBJECTIVE: The aim of this study was to compare the clinical features of major upper gastrointestinal bleeding among patients exposed to nonsteroidal antiinflammatory drugs (NSAID) and those not taking these drugs. METHODS: Using data from a multicenter international case-control study designed to evaluate the role of drugs in the etiology of major upper gastrointestinal bleeding (UGIB), patients with a confirmed first episode of major UGIB were divided into two groups: those exposed to NSAIDs during the week before the onset of bleeding, and those not exposed. The groups were compared according to age and sex, clinical appearance and site of the bleeding, preceding symptoms, and requirement for transfusion and acute surgery. RESULTS: The median age was significantly higher and the proportion of women was slightly higher among the NSAID users. There was no significant difference between users and nonusers according to the clinical presentation, the site of the bleeding, or the frequency of preceding symptoms. Forty percent in each group had no symptoms before the onset of bleeding. Slightly more NSAID users received blood transfusions, although the same median amount of blood per transfusion was given in both groups. There was no difference in the frequency of surgical intervention. CONCLUSIONS: There are no important differences in the clinical presentation of major UGIB according to whether or not an individual is an NSAID user. An important finding is the frequent absence of preceding symptoms in patients with major UGIB, regardless of NSAID use.

European network for the case-population surveillance of rare diseases (Euronet). A prospective feasibility study.

OBJECTIVE: Euronet, a case-population surveillance scheme, aims to estimate the risk of certain rare conditions which are commonly iatrogenic, by comparing drug use amongst non-selective cases with overall drug use in the general population. METHODS: The method is based on three provisos: (1) all incident cases (irrespective of suspected aetiology) should be ascertained and studied; (2) a full drug history should be obtained from cases by direct interview; and (3) drug-use data for the products of interest should be available for this population from which cases are chosen. The feasibility of this problem-oriented approach for the identification of new signals of adverse drug reactions and for risk estimation will be tested in relation to agranulocytosis, Stevens-Johnson syndrome and toxic epidermal necrolysis in four defined areas in Europe, totalling 19 x 10(6) inhabitants, with these latest two outcomes being studied in only three regions. The design, methods and main limitations of this case-population surveillance approach are described.

Drug-attributed anaphylaxis.

Allergic type I reactions to medicines range in their clinical presentation from rhinitis and urticaria to severe bronchoconstriction and anaphylactic shock. We examined all cases of suspected drug induced reactions classified as anaphylactic reactions or shock reported in Sweden between 1972 and 1995 with regard to patient characteristics and drug(s) suspected. Some comparisons with drug sales and prescription data were also made. During the study period of a total of 1338 reports concerned anaphylactic/oid shock or reactions with at least a possible causal relation to medicine giving an overall reporting rate of seven cases per million inhabitants per year of drug-induced anaphylaxis. Of these 1338 patients 51 (3.8%) died from their reactions. Among the non-fatal cases, 460 (34.4%) were diagnosed as shock and 827 (61.8%) as anaphylactic reactions. In total 46.3% of all reports concerned men but men were over-represented among the older patients and among the fatal cases (65%). There were 201 different drugs reported as 'suspected' them most common of which were dextrans (418 reports), X-ray contrast media (161 reports) and antibiotics (153 reports). For dextrans the rate of anaphylactic reactions, shock and fatal cases reported were 128,101 and 21 per million bottles respectively. This decreased to 10.3, 9.8, and 0.4 per million bottles after the introduction of preventive treatment with dextran 1 in 1983.The reporting rate for ionic contrast media were 0.14, 0.13 and 0.02 per 1000 l for reactions, shock and fatal cases respectively whilst for non-ionic contrast media they were 0.7/1000 l for reactions, 0.02/1000 l for shock, but there was no report of a fatal case. For phenoxymethylpenicillin the reported rate of anaphylaxis was 0.14 cases per million defined daily doses and for benzylpenicillin it was 3.7 cases per million defined daily doses. During the study period several drugs have been identified as important causes of anaphylaxis and measures have been taken to decrease the risk of anaphylaxis e.g. the introduction of preventive treatment with dextran 1, the shift from ionic to non-ionic contrast media and the abolition of polyethoxylated castor oil as a solvent. Spontaneous reporting of drug-induced anaphylaxis remains an important surveillance model but needs to be complemented by better quantitative methods.

Seizures and myoclonus associated with antidepressant treatment: assessment of potential risk factors, including CYP2D6 and CYP2C19 polymorphisms, and treatment with CYP2D6 inhibitors.

All adverse drug reaction reports labelled seizures or myoclonus during treatment with antidepressants and stored in the Swedish national database for spontaneous reporting of adverse drug reactions were reviewed in order to evaluate possible risk factors. The reporting physicians were contacted and asked for complementary information, and blood samples for determination of the CYP2D6 and CYP2C19 genotypes were obtained from patients available. In total, 25 cases of seizures and 7 cases of myoclonus were studied. The drugs included were maprotiline (n=8), mianserin (n=7), fluvoxamine (n=6), amitriptyline (n=3), clomipramine (n=3), citalopram (n=2), paroxetine (n=2) and lofepramine (n=1). Previously suggested predisposing factors were identified in all but four cases (87%). None of the 11 patients genotyped were found to be poor metabolizers with respect to the enzymes CYP2D6 or CYP2C19. Thus, neither the CYP2D6 nor the CYP2C19 genotype were found to be associated with the occurrence of seizures/myoclonus during treatment with antidepressants. However, 15 patients (47%) were concomitantly treated with drugs with potential inhibitory effects on CYP2D6, such as neuroleptics and dextropropoxyphene, and the patients might thus have been converted from the extensive metabolizer to the poor metabolizer phenotype during this treatment. Concomitant treatment with drugs decreasing the seizure threshold and/or inhibiting the metabolism of antidepressants appeared to be an important risk factor for the occurrence of seizures/myoclonus.

Concepts in risk-benefit assessment. A simple merit analysis of a medicine?

The term 'benefit-risk ratio' is often used as a general term linked to the use of a medicine. To balance risk and benefit is, however, a very complex exercise. For most medicines the benefits are limited to a few indications and for an individual patient there is usually only a single benefit sought but the potential risks are multiple. Perceptions of risks versus benefits are influenced to a great extent by the context in which they occur. Thus, perception of risk may be different to actual risk. In the end in any given situation, the acceptable risk-to-benefit balance is an individual judgement on the part of the patient or the prescriber. For newer medicines, where there is likely to be limited experience, conservative estimates of the overall merit seem preferable so that the prescriber will use the drug critically. Subsequently, re-evaluation of the risk-to-benefit balance is necessary as greater knowledge of efficacy and adverse effects is acquired. It is possible to provide a general 'principle of threes' structure for a merit assessment based upon the concepts of seriousness, duration and incidence as related to disease indication, disease amelioration by a medicine, and the adverse effects ascribed to the medicine. This allows a rapid first comparison of medicines for a given indication. In using this general conceptual model in a transparent fashion for a given hypothesis and context, it is possible to identify the essential data used and assumptions involved that make up a merit statement. The quality and value, particularly of risk data, is problematic. Risk perception is an issue that needs to be clearly identified alongside a merit analysis. A simple merit assessment should pave the way for more focused studies.

Drugs in the aetiology of agranulocytosis and aplastic anaemia.

Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case-control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population-based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/10(6) in the IAAAS and 0.8/10(6) in Thailand; by contrast the incidence of aplastic anaemia was 2.0/10(6) in the IAAAS and 4.1/10(6) in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/10(6) users/wk; the most strongly associated drugs were procainamide, anti-thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/10(6) users in a 5-month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug-induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.

Drug-related blood dyscrasias in a Swedish reporting system, 1985-1994.

Drug-related blood dyscrasias as reported in Sweden during a 10-yr period have been analysed in relation to sales and prescription data. The number of cases reported were as follows: agranulocytosis 390, thrombocytopenia 391, pancytopenia 50 and aplastic anaemia 36. The annual incidence rates per 10(6) inhabitants were: agranulocytosis 4.8, thrombocytopenia 5.6, pancytopenia 1.1 and aplastic anaemia 0.5. Incidences in the elderly were higher for all dyscrasias except aplastic anaemia. The most commonly reported drugs for all dyscrasias were sulphonamides and diuretics, but when related to sales data the risk of agranulocytosis was high for clozapine, dapsone, mianserin and sulphasalazine, while the risk did not seem to be increased for furosemide. For thrombocytopenia, furosemide, co-trimoxazole and the measles, mumps and rubella vaccine were most commonly reported. The risk for pancytopenia and aplastic anaemia was increased for acetazolamide and co-trimoxazole. As spontaneous reporting systems are primarily set up for signalling purposes, such data must always be interpreted with utmost care.

Alcohol consumption and the risk of major upper gastrointestinal bleeding.

OBJECTIVE: To examine the association between current alcohol consumption and major upper gastrointestinal bleeding. METHODS: In a case-control study in the United States, Sweden, and Hungary, 1004 incident cases with upper gastrointestinal bleeding without predisposing factors were compared with 2446 controls. Relative risks for categories of alcohol consumption (based on the number of drinks currently consumed/wk) were estimated using logistic regression; the potential confounding effects of cigarettes, nonsteroidal anti-inflammatory drugs, and other factors were controlled simultaneously. RESULTS: Compared with drinkers of < one drink/wk, the relative risks among other current drinkers ranged from 0.8 for 1-6 drinks/wk to 6.3 for > or = 35 drinks; the trend was statistically significant (p < 0.001). A significantly increased relative risk was seen for the heaviest consumption category within various subgroups: gastric and duodenal hemorrhage; males and females; age < 60 yr and > or = 60 yr; and those who consumed beer, wine, liquor, or a combination of beverages. CONCLUSIONS: These findings provide evidence that consumption of alcohol increases the risk of major gastric and duodenal bleeding in nonpredisposed individuals.

Acetaminophen, some other drugs, some diseases and the risk of transitional cell carcinoma. A population-based case-control study.

The purpose of this study was to investigate the risk of transitional cell carcinoma among subjects with an intake of acetaminophen, aspirin, some other drugs and with some intercurrent diseases. The source person-time ('study base') included subjects living in Stockholm in 1985-1987. The study included 325 subjects with a transitional cell carcinoma of the urinary tract and 393 controls randomly selected from the source person-time. Data were obtained by a postal questionnaire supplemented by a telephone interview. A relative risk (with a 95% confidence interval) of 1.6 (1.1-2.3) was obtained after an intake of acetaminophen, adjusted for age, aspirin, gender and smoking. Conversely, a 30% decrease in risk was obtained after an intake of aspirin. No details in the exposure substantiated the finding for acetaminophen. The inherent validity problems of observational studies, and the weak evidence in this and previous studies of the association between acetaminophen and transitional cell carcinoma, makes available epidemiological evidence insufficient to regulate the use of this commonly ingested analgesic. Increased risks were, in addition, found for tetracyclines, nitrofurantoin and a history of allergic asthma and a decreased risk found for rheumatic symptoms. The findings stress the nonepidemiological data concerning the potential carcinogenicity of acetaminophen and may be a foundation for future research of some other drugs and diseases.

Dyspnoea, asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE: To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN: Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation's international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS: Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES: Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS: In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION: Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.

Adverse experiences during treatment with zimeldine on special licence in Sweden.

Adverse experiences during licensed treatment with the antidepressant serotonin (5-HT) reuptake inhibitor zimeldine in Sweden are presented. Data were obtained from a written inquiry of 694 patients and 67 reports to the Medical Products Agency. The spectrum of adverse symptoms was in agreement with those reported in previous studies on zimeldine. The most frequent adverse experiences were headache, nausea, myalgia, signs of liver function disturbance, arthralgia, neurological symptoms, fever and insomnia. No new case of the Guillain-Barré syndrome was found. The estimated frequency of the zimeldine-induced hypersensitivity syndrome (HSS), comprising fever, myalgia and/or arthralgia and signs of liver function disturbance, ranged from 1.4% to 13% in the inquiry and from 0.63% to 3.4% in the report part of the study. Adverse experiences usually had a considerably higher incidence during the first 6 weeks of zimeldine treatment than thereafter. This is in agreement with the clinical experience that most of the adverse reactions occur early during zimeldine treatment. However, a number of adverse experiences did occur with a later onset. This may justify a prolongation of the compulsory 4 weeks' testing of liver function that is required during licensed treatment. There were significantly fewer patients who developed fever among the patients who had experienced previous zimeldine treatment than among those who had not. Otherwise there was no statistically significant difference in frequency of adverse symptoms between these two groups. Consequently zimeldine treatment per se does not seem to predispose to development of an HSS or other types of adverse reactions during subsequent therapy.