Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States.

We describe 15 cases of stricture of the colon requiring surgery in cystic fibrosis patients identified from a survey of 114 cystic fibrosis care centers in the United States. Patient ages ranged from 2 to 8 years, seven of the 15 patients were female. A history of meconium ileus was reported in nine of the 15 cases. Fibrosis of the submucosa was described in 14 surgical pathology reports. Pancreatic enzyme use history was available from 14 reports. All had taken delayed-release products for 6-96 months at average doses ranging from 6,700 to 29,100 units lipase/kg/meal, but only eight of them used products containing >20,000 units lipase per capsule prior to surgery.

Quality of adverse drug experience reports submitted by pharmacists and physicians to the FDA.

The US Food and Drug Administration (FDA)'s Spontaneous Adverse Experience Reporting System is a computerized database with over one million adverse drug experience (ADE) reports. In 1992, the FDA received over 100,000 ADE reports and pharmacists were major contributors to these reports. In 1993, the FDA launched MEDWatch, a new initiative to enhance direct reporting of adverse events by health professionals. thus far, majority of reports to MEDWatch are from pharmacists. Drug regulatory agencies of some countries do not accept reports submitted by pharmacists. We performed a study to assess the quality of information in ADE reports submitted directly to the FDA by pharmacists and physicians and compared that with manufacturer-channelled 15-day reports. We evaluated 589 ADE reports with serious outcomes associated with nine new molecular entities. Data were analysed using Epi Info. Our results showed no substantial difference in a subjective assessment of the quality of information in the reports submitted by pharmacists or physicians, irrespective of whether these reports were submitted directly or via manufacturers. This study suggests that reports from hospital pharmacists are valuable and of comparable quality. We believe that all health professionals contribute to the success of FDA's MEDWatch programme and thereby play an important part in protecting public health by promptly reporting serious adverse events.

Hepatotoxicity of antiviral agents.

Because most therapeutic agents used for viral infections are relatively new, experience with their adverse effects is still evolving. Hepatic toxicity has not been among the most important concerns with this class of drugs so far. Liver damage has been increasingly noted with accumulating experience, especially with antiretroviral drugs and those used to treat chronic hepatitis (e.g., fialuridine), but it is often difficult to distinguish between effects of therapy and of the underlying disease. It is important for clinicians to be aware of the possibility of hepatotoxicity in such situations, and further reporting of adverse experiences should contribute to more definitive evaluation of the potential influence of antivirals on liver function.

Fatal and nonfatal hepatotoxicity associated with flutamide.

OBJECTIVE: To identify and describe patients with hepatotoxicity possibly caused by flutamide, an antiandrogen drug. DESIGN: Case series of reports, submitted to the Adverse Drug Event Reporting System of the Food and Drug Administration. SETTING: Outpatient clinics and physicians' offices in the United States. PATIENTS: Nineteen patients treated with flutamide for prostate cancer or benign prostatic hypertrophy (for Investigation of a New Drug or off-label use). MEASUREMENTS: Evidence of increased liver enzyme levels, hyperbilirubinemia, associated clinical symptoms, and diagnoses of cholestatic hepatitis. Autopsy reports were used when available. RESULTS: From the time of marketing of flutamide in February 1989 through March 1991, the Food and Drug Administration received reports of 19 patients in the United States who developed serious hepatotoxicity while using flutamide. Fourteen patients had resolution of abnormal liver function test results after discontinuing or decreasing the dose of flutamide, but five patients died of progressive liver disease. Autopsy reports from three patients and abnormal pathologic results from three other patients (reported to the Food and Drug Administration or in the medical literature) showed hepatocellular necrosis and possibly cholestasis. Thorough work-ups excluded other possible causes than flutamide. CONCLUSIONS: Flutamide appears to cause hepatotoxic effects in certain patients. Physicians should tell patients to immediately report to physicians nausea, vomiting, fatigue, jaundice, and other signs and symptoms of liver injury.

Mechanism of the cardiotoxic actions of terfenadine.

OBJECTIVES AND METHODS: To gain insight into possible mechanisms of and predisposing factors for torsades de pointes during terfenadine therapy, spontaneous reports in the US Food and Drug Administration's Spontaneous Reporting System database were examined. Based on the characteristics of the cases, in vitro cardiac electrophysiologic studies were conducted to test the hypothesis that terfenadine, and not its major metabolite, has actions similar to those of quinidine and is responsible for this form of cardiac toxicity. DESIGN: Spontaneous reports from the general medical community. RESULTS: As of April 1, 1992, 25 cases of torsades de pointes had been reported to the Food and Drug Administration's Spontaneous Reporting System. Predisposing factors in these cases indicated that the parent drug, but not its metabolite, may have actions similar those of quinidine that are responsible for inducing arrhythmia. In vitro studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes. The metabolite, terfenadine carboxylate, did not inhibit this potassium current even at concentrations 30 times higher than the concentration of terfenadine producing a half-maximal effect. CONCLUSIONS: Since blockade of the potassium channel did not occur with the major metabolite of terfenadine, episodes of torsades de pointes are most likely the result of a quinidinelike action of the parent drug and of factors that impair the normally rapid metabolism of terfenadine. Dosage restriction and awareness of the clinical conditions and drug interactions capable of inhibiting the metabolism of terfenadine are essential for prevention of this serious reaction.

Hepatomegaly with severe steatosis in HIV-seropositive patients.

OBJECTIVE: To describe death attributed to severe hepatomegaly and macrovesicular steatosis without inflammation or necrosis in HIV-seropositive patients without AIDS. PATIENTS: Patients from the AIDS Clinical Trials Group (ACTG) Adverse Reactions and the Food and Drug Administration's (FDA) Spontaneous Report databases. RESULTS: Six fatal and two non-fatal cases in which no known cause of hepatic steatosis could be found were identified. With one possible exception, none of the six fatal cases had a diagnosis of AIDS and all were in reasonable nutritional status (as indicated by weight and/or serum albumin); the majority were mildly to moderately overweight. All had received at least 6 months of antiretroviral therapy, and all had gastrointestinal complaints without other non-hepatic abdominal pathology. At least three out of the six had no history of progressively abnormal liver function tests until a few weeks prior to the onset of symptoms and subsequent death. Further investigation of the FDA and ACTG databases identified two similar but non-fatal cases in which abnormalities resolved after cessation of antiretroviral therapy. CONCLUSIONS: The cases described represent a degree of hepatic abnormalities that has not been reported previously in HIV-seropositive patients, and are probably an underestimate of actual incidence, since patients with possible etiologies of liver disease were excluded from the clinical history, laboratory, microbiologic, or histologic examination. The etiology of hepatic disease may be associated with antiretroviral therapy, HIV, or an unidentifiable infection, and requires further investigation.

Chemical peritonitis following the intraperitoneal administration of vancomycin.

The Food and Drug Administration has received 51 reports of cases in the United States in which chemical peritonitis was associated with the intraperitoneal administration of sterile vancomycin hydrochloride, USP intravenous. The clinical presentation of the cases ranged from mild (cloudy dialysate alone) to more severe (severe abdominal pain and fever). The temporal circumstances suggest that intraperitoneal vancomycin may be associated with chemical peritonitis. A positive rechallenge was reported in 9 cases. The underlying mechanism responsible for this adverse reaction has not yet been identified.

Oral contraceptive oestrogen and progestin potencies and the incidence of deep venous thromboembolism.

To assess possible differences in the incidence of venous thrombosis and pulmonary embolism associated with oral contraceptives of varying hormonal potencies, the authors conducted a retrospective cohort study in the 15-44 year old Michigan Medicaid population. Cohorts were defined by the progestin- and oestrogen-potencies of oral contraceptives in use at the time of follow-up as classified by an oral contraceptive potency scheme. Using the low-oestrogen-/low-progestin-potency formulations for reference (rate ratio = 1), adjusted rate ratios of 0.8 (95% CI: 0.5 to 1.3, P = 0.41) and 0.6 (95% CI 0.4 to 1.2, P = 0.13) were observed for intermediate-progestin-potency and high-progestin-potency formulations, respectively. Adjusted rate ratios of 1.4 (95% CI: 0.8 to 2.3, P = 0.21) and 2.6 (95% CI: 1.2 to 5.5, P = 0.01) were observed for intermediate- and high-oestrogen-potency formulations. These data suggest a dose-response relationship between oral contraceptive oestrogen potency and venous thromboembolism, whereas no such evidence for a dose-response relationship between oral contraceptive progestin potency and venous thrombo-embolism was found.

Use of subsequent anticoagulants to increase the predictive value of Medicaid deep venous thromboembolism diagnoses.

Linked data bases that derive their information from health care administrative sources are increasingly being used to conduct pharmacoepidemiologic research. Computerized case ascertainment using these data would be highly advantageous in terms of time and cost considerations. For a study of oral-contraceptive-associated deep venous thromboembolism, we evaluated the utility of using anticoagulant treatment codes to validate diagnostic codes suggestive of deep venous thrombosis and pulmonary embolism. By requiring evidence of outpatient anticoagulant use within six months of hospitalization, the predictive value of case ascertainment increased from 42% to 65% for "probable" deep venous thromboembolism and from 70% to 97% for "possible" deep venous thromboembolism. In addition, use of anticoagulant treatment codes as a second marker of disease resulted in nondifferential outcome misclassification when the study base was restricted to current oral-contraceptive users. Use of confirmatory treatment claims may provide a rapid, cost-effective alternative to medical-record-based case ascertainment for pharmacoepidemiologic studies of selected outcomes conducted in Medicaid and other linked universal health care coverage populations.