An analysis of reports of depression and suicide in patients treated with isotretinoin.

BACKGROUND: The Food and Drug Administration (FDA) has received reports of depression and suicide in patients treated with isotretinoin. OBJECTIVE: Our purpose was to provide the number and describe the cases of depression and suicide reported to the FDA in US patients treated with isotretinoin and to consider the nature of a possible association between isotretinoin and depression. METHODS: An analysis was made of reports of depression, suicidal ideation, suicide attempt, and suicide in US isotretinoin users voluntarily submitted to the manufacturer and the FDA from 1982 to May 2000 and entered in the FDA's Adverse Event Reporting System database. RESULTS: From marketing of isotretinoin in 1982 to May 2000, the FDA received reports of 37 US patients treated with isotretinoin who committed suicide; 110 who were hospitalized for depression, suicidal ideation, or suicide attempt; and 284 with nonhospitalized depression, for a total of 431 patients. Factors suggesting a possible association between isotretinoin and depression include a temporal association between use of the drug and depression, positive dechallenges (often with psychiatric treatment), positive rechallenges, and possible biologic plausibility. Compared with all drugs in the FDA's Adverse Event Reporting System database to June 2000, isotretinoin ranked within the top 10 for number of reports of depression and suicide attempt. CONCLUSION: The FDA has received reports of depression, suicidal ideation, suicide attempt, and suicide in patients treated with isotretinoin. Additional studies are needed to determine whether isotretinoin causes depression and to identify susceptible persons. In the meantime, physicians are advised to inform patients prescribed isotretinoin (and parents, if appropriate) of the possibility of development or worsening of depression. They should advise patients (and parents) to immediately report mood swings and symptoms suggestive of depression such as sadness, crying, loss of appetite, unusual fatigue, withdrawal, and inability to concentrate so that patients can be promptly evaluated for appropriate treatment, including consideration of drug discontinuation and referral for psychiatric care.

Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions.

OBJECTIVE: To describe the postmarketing safety data used in the risk assessment of cisapride and to summarize the regulatory actions of the Food and Drug Administration (FDA). METHODS: The FDA analyzed reports of patients who developed QT prolongation, torsades de pointes, and ventricular arrhythmia in association with the use of cisapride to assess probable etiology and risk factors. RESULTS: While cisapride was being marketed from 1993-1999, the FDA received reports of the following patients: 117 who developed QT prolongation; 107, torsades de pointes; 16, polymorphic ventricular tachycardia; 18, ventricular fibrillation; 27, ventricular tachycardia; 25, cardiac arrest; 16, serious (unspecified) arrhythmia; and 15, sudden death; for a total of 341 individual patients affected, following use of cisapride. Eighty (23%) of the 341 patients died. Deaths were directly or indirectly associated with an arrhythmic event. Factors that suggested an association with cisapride included a temporal relationship between use of cisapride and arrhythmia, the absence of identified risk factors and other explanations for arrhythmia in some patients, and cases of positive dechallenge and rechallenge. In most individuals, the arrhythmia occurred in the presence of risk factors (other drugs and/or medical conditions). CONCLUSIONS: Postmarketing reports and pharmacokinetic and electrophysiological data provided evidence that cisapride is associated with the occurrence of QT prolongation and torsades de pointes. The risk of fatal arrhythmia with cisapride was believed to outweigh the benefit for the approved indication, treatment of nocturnal heartburn due to gastroesophageal reflux disease, leading to the drug's discontinuation in the United States.

Contraindicated use of cisapride: impact of food and drug administration regulatory action.

CONTEXT: Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. OBJECTIVE: To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. DESIGN AND SETTING: Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). PARTICIPANTS: Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. MAIN OUTCOME MEASURES: Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. RESULTS: In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. CONCLUSION: The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.

Incidence of lactic acidosis in metformin users.

OBJECTIVE: The purpose of this study was to determine the incidence of lactic acidosis in a geographically defined population of metformin users. RESEARCH DESIGN AND METHODS: The study was based on a historical cohort from the Saskatchewan Health administrative databases. Individuals with a metformin prescription dispensed between 1980 and 1995 inclusive were eligible for the cohort. Person-years of exposure were calculated. Cases were defined by hospital discharge with a diagnosis of acidosis (International Classification of Diseases, Ninth Revision code: 276.2) and confirmation by chart review of a blood lactate level > or = 5 mmol/l. Death registrations of individuals dying within 120 days of a metformin prescription were also reviewed. RESULTS: During the study period, 11,797 residents received one or more metformin prescriptions, resulting in 22,296 person-years of exposure. There were 10 subjects who had hospital discharges with a diagnosis of acidosis. However, primary record review revealed only two cases with laboratory findings of elevated blood lactate levels, for an incidence rate of 9 cases per 100,000 person-years of metformin exposure. In both cases, other factors besides metformin could have contributed to the lactic acidosis. No additional cases were found on review of death registrations. CONCLUSIONS: From 1980 through 1995, the incidence rate of lactic acidosis was 9 per 100,000 person-years (95% CI 0-21) in patients dispensed metformin in Saskatchewan, Canada. This incidence rate was derived from a population with complete ascertainment of hospitalizations and deaths associated with lactic acidosis in metformin users. It is similar to previously published rates based on passive reporting of cases, and it is well below the lactic acidosis rate of 40-64 per 100,000 patient-years in patients prescribed phenformin.

Flutamide hepatotoxicity.

PURPOSE: Observed and expected reporting rates were compared in patients who died or were hospitalized due to hepatotoxicity associated with the use of flutamide. MATERIALS AND METHODS: Case series were submitted to the MedWatch Spontaneous Reporting System of the Food and Drug Administration. Reporting rates for serious hepatotoxicity due to flutamide were calculated and compared to rates for hospitalized patients with acute idiopathic hepatitis in the medical literature. RESULTS: After the marketing of flutamide in the United States, between February 1989 and December 1994 the Food and Drug Administration received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. The rate of approximately 3 per 10,000 flutamide users exceeds by 10-fold or more the expected rate of hospitalizations for acute noninfectious liver injury of 2.5 per 100,000 men 65 years and older. Autopsies in 6 cases revealed marked to massive hepatic necrosis as the predominant feature. CONCLUSIONS: Flutamide is a potent hepatotoxin in certain patients. Serial blood aminotransferase levels should be monitored during the first few months of flutamide treatment. Before beginning use of this drug patients should be instructed to report immediately to physicians any episodes of nausea, vomiting, fatigue and jaundice so that flutamide can be promptly discontinued to avoid progression of possible liver injury.

Sedative-hypnotic drugs and the risk of hip fracture.

A retrospective cohort study was conducted in individuals 65 years of age and older using Medicaid-reimbursed claims to assess the risk of hip fracture in users of two sedative-hypnotic drugs, triazolam and temazepam. Using the triazolam cohort as the referent group, the rate ratio was 0.92 (95% confidence interval, 0.72 to 1.17) for hip fracture with temazepam. Stratifying by age, sex, race, residence, time enrolled in Medicaid, prescription number, combinations of these, and several other potential confounding variables did not materially change the results. Compared with the short-acting benzodiazepine hypnotic temazepam, use of triazolam, an ultra-short-acting benzodiazepine hypnotic, did not decrease the risk of hip fracture. This study did not determine that either drug, compared with no use in an insomniac control group, increases the risk of hip fracture. However, because sedative-hypnotic drugs have been found in other studies to increase the risk of falling and hip fracture, they should be used with caution, especially in the elderly.

Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone.

We report 13 cases of benign intracranial hypertension (IH) in children with growth hormone (GH) deficiency treated with GH in the United States. The group consisted of eight boys and five girls, 3 to 16 years of age (median, 9 years). The interval from starting GH therapy to diagnosis of IH was 2 weeks or less in six patients, between 2 and 12 weeks in four, 8 months in one, 5 years in one, and unknown in one. Seven patients were not known to have previously described IH risk factors; the other six had at least one factor each. All patients but one had headache, nausea, vomiting, and visual changes. All had papilledema, and cerebrospinal fluid pressures were elevated (> 250 mm H2O) in all nine patients tested. The GH dosage range was 0.17 to 0.35 mg per kilogram body weight per week (median, 0.30 mg/kg per week) for the 11 patients with dosage data. After discontinuation of GH and treatment with lumbar punctures and/or medications, signs and symptoms resolved in eight children; in two of these children signs and symptoms reappeared when GH therapy was restarted. In four patients signs and symptoms resolved while GH therapy was continued; one child was treated with a ventriculoperitoneal shunt because of an arachnoid cyst, after which GH was restarted without subsequent IH. In the 12 patients with idiopathic GH deficiency the course of IH was benign, with complete resolution of all signs and symptoms. Because doses and scheduling of GH administration have changed since the introduction of recombinant GH, higher doses and increased frequency of administration may be contributing to the development of IH in some patients. We suggest beginning therapy at the lowest recommended dose, with gradual titration to higher doses, and the performance of routine funduscopic examinations during initiation of GH therapy and whenever signs or symptoms of IH develop.

Serious adverse events in Norplant users reported to the Food and Drug Administration's MedWatch Spontaneous Reporting System.

OBJECTIVE: To describe serious adverse events in Norplant users from reports submitted to the Food and Drug Administration's (FDA) MedWatch Spontaneous Reporting System. METHODS: Reports of certain serious adverse events in Norplant users in the United States from February 1991 to December 1993 were reviewed and analyzed. RESULTS: From the introduction of Norplant in the United States in February 1991 to December 1993, the FDA received reports of 24 women hospitalized for infections at the insertion site, 14 hospitalized or disabled because of difficulties removing the capsules, 14 hospitalized for stroke, three for thrombotic thrombocytopenia purpura, six for thrombocytopenia, and 39 for pseudotumor cerebri. The comparison of reported rates with expected rates and the relationship of some of these disorders with oral contraceptives raises the suspicion of a causal association with Norplant. CONCLUSIONS: The FDA has received reports of hospitalization or disability for infections, capsule removal difficulties, stroke, thrombotic thrombocytopenia purpura, thrombocytopenia, and pseudotumor cerebri in Norplant users. Health care professionals need to be trained in Norplant insertion and removal to ensure the proper technique. Studies are needed to determine if stroke, thrombocytopenia, and pseudotumor cerebri are causally related to Norplant use.

Use of menopausal estrogens and medroxyprogesterone in the United States, 1982-1992.

OBJECTIVE: To describe trends in the prescription of menopausal estrogens and medroxyprogesterone in the United States. METHODS: Annual estimates of the number of prescriptions for menopausal estrogens and medroxyprogesterone and descriptive information on patients and providers were obtained from two pharmaceutical marketing research data bases, the National Prescription Audit and the National Disease and Therapeutic Index of IMS America. RESULTS: An estimated 13.6 million prescriptions were dispensed for oral menopausal estrogens in 1982, and 31.7 million in 1992, a 2.3-fold increase (P = .0001). In 1992, Premarin, the only oral conjugated estrogen currently approved for use, was the most frequently dispensed brand-name pharmaceutical in the United States. Dispensed prescriptions for Estraderm, a transdermal estradiol first marketed in 1986, increased from 1.5 million in 1987 to 4.7 million in 1992. Dispensed prescriptions for oral medroxyprogesterone also increased from 2.3 million prescriptions in 1982 to 11.3 million in 1992, a 4.9-fold increase (P = .0001). An estimated one in six to one in four postmenopausal women were taking menopausal hormones in 1992. These drugs were prescribed mainly by obstetrician-gynecologists. CONCLUSION: The use of menopausal estrogens and medroxyprogesterone has increased substantially over the past decade. These trends indicate that American women are widely exposed to menopausal hormone replacement.

Use of fertility drugs in the United States, 1973 through 1991.

There has been a 1.9-fold increase over nearly 20 years in the number of dispensed prescriptions for CC. Since its marketing in 1967, CC has been the major drug prescribed for infertility. In 1973, there were an estimated 390,000 prescriptions for this drug; by 1991, 731,000. From 1984 through 1991, chorionic gonadotropin, menotropins, and urofollitropin together accounted for no more than one third of the market share of the gonadotrophin class of drugs, whose primary indication is treatment of infertility. These drugs were primarily prescribed by obstetrician gynecologists to white females, 20 to 39 years of age, for treatment of infertility of unspecified origin.

Risk of leukemia after treatment with pituitary growth hormone.

OBJECTIVE: To determine whether pituitary-derived human growth hormone treatment increases the subsequent risk of developing leukemia and lymphoma. DESIGN: Cohort study. SETTING: United States. PARTICIPANTS: A total of 6284 recipients of pituitary-derived human growth hormone distributed by the National Hormone and Pituitary Program between 1963 and 1985. MAIN OUTCOME MEASURES: Leukemia and lymphoma. RESULTS: Three cases of leukemia occurred in 59,736 patient-years of follow-up from the start of growth hormone therapy to case ascertainment at interview; this number was not significantly higher (P = .23) than the 1.66 cases expected in the US age-, race-, and gender-matched general population. Three additional cases, found in an extended follow-up that provided 83,917 person-years of risk, yielded a minimum rate of leukemia that was significantly increased (six cases found, 2.26 expected; P = .028). The relative risk of leukemia in pituitary growth hormone recipients compared with the general population was 1.8 (90% confidence interval [CI], 0.82 to 7.5) for the defined follow-up and 2.6 (90% CI, 1.2 to 5.2) for the extended follow-up. Five of the six subjects who developed leukemia had antecedent cranial tumors (four craniopharyngioma, one astrocytoma) as the cause of growth hormone deficiency, and four had received radiotherapy. There was no increase in leukemia in patients with idiopathic growth hormone deficiency. The association of leukemia and craniopharyngioma was significant (P < .001). There was no excess of lymphoma in the cohort. CONCLUSIONS: This cohort of growth hormone recipients had a significantly increased rate of leukemia compared with the age-, race-, and gender-matched general population. However, the upper bound CI of the relative risk in our population (5.2) is well below the other estimates (7.6). Compared with the general population, our study population had more possible risk factors for leukemia (radiation, tumor) that may have contributed to the excess observed. The clustering of cases of leukemia in craniopharyngioma patients should be further evaluated.

Mortality attributed to misuse of psychoactive drugs, 1979-88.

To assess mortality attributed to misuse of psychoactive drugs in the United States from 1979 through 1988, the authors obtained from death certificates the annual number of, and age-, sex-, and race-specific data for, deaths in which psychoactive drugs were coded as the underlying or contributing cause. Deaths with psychoactive drugs specified as underlying cause (drug-induced) increased from 6,500 (2.9 per 100,000) in 1979 to more than 10,000 (3.8 per 100,000) in 1988. Deaths with psychoactive drugs specified as either underlying or contributing cause (drug-related) increased from 7,200 (3.2 per 100,000) in 1979 to more than 14,400 (5.5 per 100,000) in 1988. The drugs that primarily accounted for this increase were illicit, in particular, the opiates (heroin) and cocaine, with most of the remainder accounted for by misuse of various legal drugs. The largest increases between 1979 and 1988 occurred among black men ages 35-44 whose drug-induced death rates rose from 8 to 36 per 100,000 and whose drug-related death rates from 10 to 82 per 100,000. These data identify a high-risk group for targeting efforts to prevent deaths due to misuse of psychoactive drugs.

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.