Trends in Erythropoiesis-stimulating agent use and blood transfusions for chemotherapy-induced anemia throughout FDA's risk evaluation and mitigation strategy lifecycle.

PURPOSE: Erythropoiesis-stimulating agents (ESAs), indicated for treating some patients with chemotherapy-induced anemia (CIA), may increase the risk of tumor progression and mortality. FDA required a Risk Evaluation and Mitigation Strategy (REMS) to mitigate these risks. We assessed REMS impact on ESA administration and red blood cell (RBC) transfusion as surrogate metrics for REMS effectiveness. METHODS: Retrospective cohort study including data from January 1, 2006 to December 31, 2018 for beneficiaries ≥65 years enrolled in Centers for Medicare & Medicaid Services (CMS) Medicare Parts A/B with a cancer diagnosis; patients with other indications for ESA use were excluded. Study time was divided into five periods demarcated by issuance of CMS National Coverage Determination (NCD) (Pre-NCD, Pre-REMS) and REMS milestones (Grace Period, REMS, post-REMS). Study outcomes were monthly proportion of chemotherapy episodes (CTEs) with concomitant ESA administration, with post-CTE ESA administration, and with RBC transfusions. RESULTS: Of 1 778 855 beneficiaries treated with CT, 308742 received concomitant ESA for CIA. The proportion of CTEs with concomitant and post-CTE ESA administration decreased Pre-REMS (9.0 percentage points [pp] and 3.5 pp, respectively). There were no significant post-REMS changes in the proportion of CTEs with concomitant (0.0 pp) and post-CTE ESA administration (0.1 pp). Fluctuation in RBC transfusions was <4 pp throughout the study period. CONCLUSIONS: Medicare beneficiaries showed a substantive decrease in ESA administration after NCD, with minimal impact by the REMS and its removal. Small changes in RBC transfusion over the study period were likely due to a national secular trend.

Use of isotretinoin (Accutane) in the United States: rapid increase from 1992 through 2000.

BACKGROUND: Isotretinoin, a drug approved to treat severe recalcitrant nodular acne, has been marketed in the United States since 1982. The drug is an effective treatment for acne that is refractory to other therapies, but it is a teratogen and can cause serious side effects. OBJECTIVE: Our purpose was to describe trends in the use of isotretinoin in the United States from marketing through year 2000 and summarize characteristics of patients and prescribers. METHODS: Data from 2 pharmaceutical marketing research databases, the National Prescription Audit Plus and the National Disease and Therapeutic Index, and from 2 health plan networks were obtained and analyzed. RESULTS: Retail pharmacies dispensed 19.8 million outpatient prescriptions for isotretinoin from marketing in 1982 through 2000. From 1983 through 1993, the median annual number of prescriptions was just over 800,000; between 1992 and 2000, the number of prescriptions increased 2.5-fold (250%) to nearly 2 million in year 2000. The increases registered in the health plans were somewhat larger: about 275% increases from 1995 through 1999. There is no ICD-9 code for nodulocystic acne; consequently, the type of acne treated with isotretinoin is not determinable from these data. However, between 1993 and 2000, the proportion of isotretinoin treatment for severe acne declined from 63% to 46%, whereas the proportion of treatment for mild and moderate acne increased from 31% to 49%. Data also indicated that the sex distribution of patients was nearly even, and that 63% of male patients prescribed isotretinoin were 15 to 19 years old, whereas 51% of female patients were 15 to 24 years old. CONCLUSION: In the last 8 years, there has been a 2.5-fold (250%) increase in the number of dispensed prescriptions for isotretinoin in the United States. Data also reveal an increasing proportion of isotretinoin use for mild and moderate acne.

Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment.

BACKGROUND: Adverse pregnancy outcomes following the use of angiotensin-converting enzyme (ACE) inhibitors, including enalapril, have been reported in descriptive studies. However, no analytical studies on the relationship between the adverse outcomes and enalapril gestational exposures are available. OBJECTIVES: To explore the association between enalapril exposure and adverse outcomes in pregnancy, taking into account other possible risk factors. METHODS: We analyzed a series of all usable cases reported to the FDA between 1986 and 2000 in which enalapril was a suspect drug for the observed adverse outcomes (N = 110). Parameters of exposure and reported outcomes as well as information on potentially confounding variables were systematically abstracted from this series by a single physician. Because exposure to ACE inhibitors after the first trimester of pregnancy had been associated with adverse outcomes in the existing literature, we divided the cases into those exposed in the first trimester only (considered as the baseline group) and cases exposed beyond or after this time. Frequency of reported adverse outcomes in the second group was compared with those in the baseline group; odds ratios were computed, taking account of potentially confounding variables by logistic regression where appropriate. RESULTS: Exposure to enalapril after the first trimester of pregnancy was strongly associated with oligohydramnios and specific adverse outcomes thought to be secondary to reduced amniotic fluid volume (limb deformities, cranial ossification deficits, lung hypoplasia), as well as with neonatal renal failure. The relationship did not change after taking numerous potential confounders into account, including duration of exposure, concomitant drug use, maternal age, concurrent disease, neonatal gender, and gestational age at birth. Such a pattern of abnormalities is considered to be a consequence of the effect of ACE inhibition on fetal renal function that develops after the first trimester. CONCLUSION: The specificity and temporality of the observed adverse manifestations suggest a causal relationship to enalapril exposure.