Troglitazone (Rezulin) and hepatic injury.

PURPOSE: Analyze US rates of reported severe liver disease for the oral hypoglycemic agent troglitazone from March 1997 through February 2000 and the possible effects of publicity on reporting. METHODS: The number of troglitazone reports with liver failure and or hospitalization with jaundice or hyperbilirubinemia, made to the FDA and/or Parke-Davis are used as numerators. The denominators are numbers of patients and person-time estimates of exposure. Additionally, the amount of publicity about troglitazone during its marketing is quantified. RESULTS: Approximately 1.92 million patients were treated with troglitazone from March 1997 through the end of February 2000 resulting in 1.6 million person-years of exposure. Reports of 83 cases of liver failure associated with troglitazone were received (1 in 23,000 patients or 1 in 20,000 person-years). Of the 83 cases, only 49 (59%) were classified by a hepatologist to be 'possibly' or 'probably' attributed to troglitazone. For the first, second, and third years of marketing, rates of reported hepatic failure per 100,000 person years exposure to troglitazone were 8.3, 5.3, and 2.7 respectively. Rates of reported liver disease involving hospitalizations with mention of jaundice and hyperbilirubinemia per 100,000 person-years were 16.0, 6.1, and 3.6 respectively for these years. During the 3-year marketing history of troglitazone, there were 470 lay press and 158 medical literature articles with mentions of hepatotoxicity for the drug. CONCLUSIONS: Rates of reported severe liver disease declined substantially during the second and third years of marketing of troglitazone. The decline followed increasingly stringent requirements for liver function test monitoring and may have been due to improved patient selection and management as a result of the widely publicized association between troglitazone and hepatotoxicity.

Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study.

CONTEXT: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because of inhibition of cyclooxygenase (COX)-1. Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown. OBJECTIVE: To determine whether celecoxib, a COX-2-specific inhibitor, is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs. DESIGN: The Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind, randomized controlled trial conducted from September 1998 to March 2000. SETTING: Three hundred eighty-six clinical sites in the United States and Canada. PARTICIPANTS: A total of 8059 patients (>/=18 years old) with osteoarthritis (OA) or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received at least 1 dose of study drug. A total of 4573 patients (57%) received treatment for 6 months. INTERVENTIONS: Patients were randomly assigned to receive celecoxib, 400 mg twice per day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987); ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per day (n = 1996). Aspirin use for cardiovascular prophylaxis (

Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans.

Use of recombinant human erythropoietin in patients with end-stage renal disease has highlighted iron deficiency as the major cause of resistant anemia. The current mainstay of intravenous (i.v.) iron replacement therapy, iron dextran, has been shown in prior studies to have a risk of serious life-threatening anaphylaxis of just under 1 per 100 patients exposed. The current study assessed the safety profile of an alternative i.v. iron, sodium ferric gluconate complex in sucrose (Ferrlecit), as compared with iron dextrans. Sodium ferric gluconate complex in sucrose, a unique chemical preparation, has been in use since 1959, principally in Europe, at a rate of approximately 2.7 million i.v. doses per year (1992 to 1996) in Germany and Italy alone. For iron dextran, usage in the United States was comparable--principally renal hemodialysis--and estimated from market sources at 3.0 million doses per year (1995). From 1976 to 1996, there were 74 allergic adverse events reported for sodium ferric gluconate complex in sucrose to the World Health Organization (WHO), German Health Bureau, and the manufacturer (all combined). For the years 1992 to 1996, sodium ferric gluconate complex in sucrose had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the United States in 1995. Case fatalities for sodium ferric gluconate complex in sucrose and iron dextran within these reports were then compared. For sodium ferric gluconate complex in sucrose, there were no reports of deaths over the entire period (1976 to 1996). However, for iron dextrans, there were 31 fatalities among 196 allergy/anaphylaxis cases reported in the United States between 1976 and 1996, yielding a case-fatality rate of 15.8%. These data show that sodium ferric gluconate complex in sucrose, when compared with iron dextrans in comparably sized patient usage populations with similar total rates of reporting of allergic events, has a significantly lower reported mortality rate (P < 0.001). Thus, the data justify usage of sodium ferric gluconate complex in sucrose as the safer iron replacement therapeutic agent.

Verapamil use in patients with cardiovascular disease: an overview of randomized trials.

BACKGROUND: Several reports have questioned the lack of safety data on calcium antagonists as a drug class. Because this drug class is heterogeneous, unique features of certain calcium antagonists may set them apart in terms of safety and efficacy. HYPOTHESIS: With in excess of 7,000 person-years of observation from randomized clinical trials, verapamil was selected to evaluate whether there was evidence of harm in patients with cardiovascular disease. METHODS: MEDLINE search of English-language articles, Science Citation Index, Current Contents, manual review of cited references, pharmaceutical files, and investigator correspondence was performed. Independent review of 66 articles identified 14 randomized, parallel-group studies for inclusion. Independent, duplicate assessments were made of patient outcomes and trial characteristics (including study design, treatment dosage and schedule, duration of treatment, inclusion criteria, and sample size). Standard meta-analytic techniques were employed for analysis and interpretation of results. RESULTS: Based on over 4,000 person-years of observation, patients with acute myocardial infarction (MI) treated with verapamil had a decreased risk of nonfatal reinfarction compared with placebo (relative risk 0.79; 2-sided 95% confidence interval 0.65.0.97; p = 0.024). Verapamil had no significant effect on overall mortality compared with placebo (relative risk ranged from 0.93; 2-sided 95% confidence interval 0.78, 1.10; p = 0.40 to 0.86; 2-sided 95% confidence interval 0.71, 1.04; p = 0.13) depending on rules used to include or exclude patients from the pooling process. For the combined outcome of death or reinfarction, verapamil use was associated with a decreased risk compared with placebo (relative risk 0.82; 2-sided 95% confidence interval 0.70, 0.97; p = 0.016). In patients with angina involving a wide spectrum of disease severity, data were limited to 2,900 person-years of observation, and verapamil use did not appear to be associated with an apparent effect on mortality or MI. Data available from randomized studies of verapamil in patients with hypertension were too limited to reach conclusions (50 person-years of observation, with no deaths or MIs reported). Subgroups of hypertensive patients in two of the largest post-MI studies and the largest angina study, involving over 600 patients, yielded little useful added information. CONCLUSIONS: In patients with MI, the risks of both nonfatal reinfarction and the combined outcome of death or nonfatal MI were reduced over intermediate-term follow-up among patients treated with verapamil compared with controls (p = 0.024 and p = 0.016, respectively). In patients with angina, no evidence for harm was noted, but in hypertension the data were too limited to draw conclusions. These findings support the need to distinguish among different calcium antagonist compounds and to emphasize the need for more data in patients with hypertension.

Effect of onychomycosis on quality of life.

BACKGROUND: Onychomycosis impairs normal nail functions, causes considerable pain, interferes with daily activities, and has negative psychosocial effects. OBJECTIVE: Our purpose was to determine patients' perception of onychomycosis on the quality of life. METHODS: A total of 258 patients with confirmed onychomycosis were surveyed by telephone at three centers. Responses to a standardized quality-of-life questionnaire were analyzed for patient demographics, physical and functional impact, psychosocial impact, and economic impact. RESULTS: Highest positive responses were nail-trimming problems (76%), embarrassment (74%), pain (48%), nail pressure (40%), and discomfort wearing shoes (38%). Ability to pick up small objects was impaired in 41% of subjects with fingernail involvement. More than 58 onychomycosis-related sick days and 468 medical visits (1.8 per subject) were reported during a 6-month period. CONCLUSION: Onychomycosis has significant social, psychologic, health, and occupational effects. Relevance of quality-of-life issues to overall health, earning potential, and social functioning should prompt reconsideration of the value of aggressive treatment of and financial coverage for onychomycosis.

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.

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).

Effects of exposure to benzodiazepine during fetal life.

Dysmorphism and mental retardation have been reported in 7 Swedish children born of mothers who had taken high doses of benzodiazepines regularly during pregnancy. To explore this association further, we examined benzodiazepine use during pregnancy in 104,000 women whose deliveries were registered by the US public health insurance system, Medicaid, during 1980-83. Fetal outcomes were assessed from the health claims profiles of their offspring, up to 6-9 years after delivery. 80 pregnant women had received 10 or more benzodiazepine prescriptions during the 4 years. Their records showed heavy general use of health care and frequent alcohol and substance abuse, and other disorders that could confound any effect of the benzodiazepines. For the 80 pregnancies, 3 intrauterine deaths were identified as well as 2 infants with congenital abnormalities whose curtailed records suggested neonatal death. Records of 64 surviving children could be linked to these 80 pregnancies whilst records for 11 apparent survivors could not be located. 6 of the 64 survivors had diagnoses consistent with teratogenic abnormalities. The high rate of teratogenicity after heavy maternal benzodiazepine use occurs with multiple alcohol and substance exposure and thus may not be due to benzodiazepine exposure.

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.