Clustering of adverse drug events: analysis of risk factors for cerebellar toxicity with high-dose cytarabine.

BACKGROUND: Cerebellar toxicity is a severe, therapy-limiting adverse reaction of cytarabine given in high doses. The Food and Drug Administration received a report of an increased frequency of cerebellar toxicity at the University of Wisconsin Hospital and Clinics after a switch from the product (Cytosar-U) manufactured by The Upjohn Co., Kalamazoo, Mich., to the generic form made by Quad Pharmaceuticals, Inc., Indianapolis, Ind. PURPOSE: To compare the incidence of cerebellar toxicity in Quad-treated patients with Upjohn-treated patients, a record-based cohort study was conducted at the University of Wisconsin Hospital and Clinics between January 1986 and August 1989. METHODS: The incidence of cerebellar toxicity was studied in 63 leukemia patients according to the manufacturer of the product received (34 Upjohn only, 25 Quad only, and four both manufacturers). The relative risk of cerebellar toxicity was adjusted for other known risk factors. RESULTS: Patients in the manufacturer-defined treatment groups did not differ significantly with respect to age, sex, type of leukemia, disease stage, calculated creatinine clearance, presence of abnormal liver function tests, or total dose received. The crude relative risk of cerebellar toxicity comparing the Quad product with the Upjohn product was 5.0 (95% confidence interval = 1.8-13.7). Adjustment for potential confounders did not alter the association. Other risk factors for cerebellar toxicity, independent of manufacturer, were age greater than 50 years, type of leukemia, disease stage, total dose greater than or equal to 20 g/m2, abnormal pretreatment liver function, and reduced creatinine clearance. CONCLUSION: This study found a significantly higher incidence of cerebellar toxicity with high-dose cytarabine manufactured by Quad Pharmaceuticals when compared with the incidence of cerebellar toxicity with the Upjohn product. Further research at independent institutions would be necessary to allow generalization of this finding. In addition, our findings suggest that a dose reduction in high-dose cytarabine therapy may be indicated for patients with reduced glomerular filtration rates.

National adverse drug reaction reporting. 1984-1989.

Surveillance of adverse reactions due to pharmaceuticals is important because the drug approval process cannot totally assure safety and because new knowledge is bound to accrue after drugs enter usual medical practice. Reporting of reactions to the Food and Drug Administration increased markedly between 1985 and 1989 and totaled 261,515 reports for this period. A large part of this increase was due to new legal requirements, which ensure that manufacturers report reactions to the Food and Drug Administration. Most reaction reports originated with practicing physicians who contacted drug manufacturers. High proportions of the reports involved new drugs and serious reactions. Reaction surveillance leads to 50 to 100 important safety investigations annually and to numerous changes in product information. Health care providers must continue to report suspect adverse reactions to the Food and Drug Administration and manufacturers if pharmaceutical use and safety are to improve.

National adverse drug reaction surveillance. 1986.

The collection of adverse drug reaction (ADR) reports by the Food and Drug Administration serves to provide additional information on the toxic reactions of drugs that often cannot be known before a drug is marketed. In 1986, a total of 53,547 ADR reports were received; 56% of these were made by US health care professionals based on observations made during usual clinical practice. The 1986 total represents an increase of 14% in ADR reporting over 1985, continuing a trend begun in 1981. While these increases are encouraging, US reporting rates are far below many other countries, and further encouragement of reporting must be done. Of these ADR reports, 24% involved serious reactions and 20% involved new drugs. An ADR report should be seen as a professional responsibility; reports are carefully analyzed and used.

Incidence and hospitalization patterns of insulin-dependent diabetes mellitus.

Data from a statewide insulin-dependent diabetes mellitus (IDDM) registry in Rhode Island show that IDDM affects young adults (20-29 yr) as frequently as adolescents and teenagers (10-19 yr). Overall incidence less than 30 yr was 14/100,000 population. Peak incidence occurred at 10-14 yr (19/100,000 population). Poor diabetic control and infection accounted for 46-62% of hospitalizations among 275 known diabetic persons. Despite a 10-yr mean duration of diabetes, only 31% of hospitalized diabetic persons less than 30 yr of age reported ever having received outpatient diabetes education of two or more hours. Readmissions 1 yr after initial registration were more frequent for known (43%) than new-onset (18%) IDDM cases. Increased risk of readmission for both groups was associated with a poverty socioeconomic status. Total direct hospitalization costs for IDDM in persons under 30 yr of age in Rhode Island was $530,000 per year of $2,245 per patient.

National patterns of aspirin use and Reye syndrome reporting, United States, 1980 to 1985.

The number of cases of Reye syndrome reported annually to the Centers for Disease Control declined markedly between 1980 and 1985. In this article, we present pharmaceutical marketing research data that suggest sharp decreases in the use and purchase of children's aspirin between 1980 and 1985. These trends appear to correspond to the decrease in reporting of Reye syndrome cases. Additionally, analysis of physician mentions of aspiring and acetaminophen for treating flu and chickenpox showed statistically significant trends toward decreasing recommendations for the use of aspirin and significant trends toward increasing recommendations for use of acetaminophen. Trends in wholesale purchases of aspirin and acetaminophen by drug stores from 1979 through 1985 demonstrated a significant decline for the 81-mg children's aspirin tablet and an increase in purchases of children's acetaminophen products. Many factors may influence physician and parents' choice of analgesic/antipyretic medication, including information about Reye syndrome. Data suggest that a continuing decline in the use of aspirin for children may be accompanied by a continuing decline in the reported number of Reye syndrome cases.

Morbidity and mortality among low birth weight infants exposed to an intravenous vitamin E product, E-Ferol.

In April 1984, the US FDA was notified of an unusual clinical syndrome consisting of ascites, liver and renal failure, thrombocytopenia, and death among low birth weight infants exposed to an intravenous vitamin E preparation, E-Ferol. The product, which had not been tested for safety prior to marketing, was voluntarily withdrawn from the market in early April. To further investigate the reported associations, the FDA conducted a retrospective cohort study among seven neonatal intensive care units where the product had been used. Standardized abstraction forms were completed for infants admitted to a unit between Nov 1, 1983, and April 30, 1984. Included in the study were 379 infants weighing 2,000 g or less and surviving at least two days; 148 (39%) had been exposed to E-Ferol. Compared with the unexposed infants, the exposed infants were more likely to die and to have ascites, hepatomegaly, thrombocytopenia, and a combination of clinical events similar to the syndrome initially reported. We conclude that the use of E-Ferol in these neonatal intensive care units was associated with increased morbidity and mortality among exposed infants.

Terfenadine-associated ventricular arrhythmias and QTc interval prolongation. A retrospective cohort comparison with other antihistamines among members of a health maintenance organization.

This study compared the occurrence of syncope, ventricular arrhythmias, and corrected QT interval (QTc) prolongation over a 2 1/2-year period in persons prescribed terfenadine versus other prescription antihistamines among 265,000 members of the Harvard Community Health Plan (HCHP), the largest staff-model health maintenance organization in New England. HCHP maintains an automated medical record system with coded diagnoses for each ambulatory and hospital visit, and a similar automated pharmacy system with information for each member on all prescriptions filled at its pharmacies. Among 0.86 million exposure days of terfenadine and 1.04 million exposure days of other antihistamines, we found no excess risk of either clinical/arrhythmia events (odds ratio (OR), 0.86; 95% confidence interval (CI), 0.52 to 1.44) or QTc prolongation (OR, 1.00; 95% CI, 0.64 to 1.57) during courses of terfenadine versus those of other antihistamines. Joint courses of antihistamines and oral erythromycin were associated with an increased risk of QTc prolongation (OR, 2.33; 95% CI, 1.31 to 4.15), and there was a trend for this to be observed more frequently with terfenadine (OR, 2.37; 95% CI, 0.73 to 7.51; P = 0.14).

A method of pharmacoepidemiologic analysis that uses computerized Medicaid.

A method of pharmacoepidemiologic data analysis that utilizes computerized Medicaid data is presented. A cohort design in which Medicaid enrollees receiving drugs that are normally used to treat similar underlying conditions is described. A period of time in which Medicaid service transactions are evident is required before an individual is eligible for selection into a cohort. Selection of study subjects and descriptions of cohorts are based on Medicaid service histories occurring during the preliminary, prerequisite period. Time at risk is considered to begin after a prescription for a study drug is dispensed and continues until either a refill is dispensed, a prescription for an alternative drug within the same therapeutic class is dispensed, or a predetermined number of days has passed. Subjects are followed forward in time and relevant health care transactions that are suggestive of suspected adverse drug reactions are noted. Incidence densities associated with sequentially ranked prescriptions within sequential courses of therapy are compared. Methods to increase the accuracy of case ascertainment are briefly discussed. Separate validation studies may be used to evaluate the validity of computerized case ascertainment methods and to compensate for misclassification of outcome. The proposed method is intended to provide timely estimates of risk for selected outcomes. For outcomes that cannot be accurately ascertained from computerized data, this method may be useful in determining the feasibility of more customized studies.

The prevalence and relationships of malaria, anemia, and malnutrition in a coastal area of El Salvador.

To study the relationships between malaria, anemia and malnutrition, 853 school-age children from a high malaria incidence area and an adjacent low incidence area were surveyed in September 1972. For the high incidence area the malaria slide positivity rate was 3.5%, spleen rate 7.6% and malaria (indirect fluorescent antibody) serology positivity 24.7%. Contrasted to this, no positive slides, only 3 palpable spleens and a 3.4% serology positivity rate were found for the low incidence area. Twenty-three percent of those studied were anemic, but the prevalence of anemia was the same in both the high and low incidence areas. However, a selected group of children with known history of recent or actual malaria was found to be more likely to have deficient hematocrit values than were children without such history. Hypochromia and microcytosis were prominent morphologic findings in children with anemia, suggesting a diagnosis of iron deficiency. Weights and heights for age were considerably below those of a U.S. reference population but similar to nationwide Salvadoran figures. In both the high and low incidence groups, 62% had arm circumference values below 90% of standard. The distribution of weight-to-height ratios was also similar for both groups. No difference in nutritional status between the two groups could be found.

Risks and indications of phenylbutazone: another look.

In 1984 an extensive review of phenylbutazone risks was undertaken by the Food and Drug Administration (FDA). Since that review, new recommendations for the drug's use have been published. Marketed in 1952, phenylbutazone has long been recognized as capable of inducing aplastic anemia. The risk of marrow depression is greatest in elderly females treated for over a month. Overall, the risk does not exceed that of many commonly used drugs (e.g., penicillin, which induces anaphylaxis). Nonetheless, phenylbutazone should not be a drug of first choice and should not be used for minor, self-limited conditions.

US adverse drug reaction surveillance 1989-1994.

Adverse drug reaction surveillance conducted by the US Federal Food and Drug Administration (FDA) is important for detecting new safety information about pharmaceuticals. FDA has sought to stimulate reporting of reactions by practitioners and manufacturers. Over the five years from 1989 to 1993, reporting more than doubled and a total of 421,491 reports were received. This trend continued in 1994. The origin, type of reaction and drug are presented. Most reports are made by health professionals through pharmaceutical manufacturers. About 5% of such reports involve serious reactions to new drugs. Uses and limitations of ADR surveillance are briefly discussed.

Asbestos hazard evaluation in Rhode Island schools.

A statewide survey to identify and abate spray-on asbestos hazards in schools has been conducted in Rhode Island. Of 326 target schools, 24 (8 per cent) contained material confirmed in the laboratory to be spray-on asbestos. Overt hazards requiring major corrective measures were found in 4 (1 per cent) of the target schools. Simplified identification and reporting procedures allowed for the efficient conduct of the survey.