Emergency hospitalizations for unsupervised prescription medication ingestions by young children.

BACKGROUND: Emergency department visits and subsequent hospitalizations of young children after unsupervised ingestions of prescription medications are increasing despite widespread use of child-resistant packaging and caregiver education efforts. Data on the medications implicated in ingestions are limited but could help identify prevention priorities and intervention strategies. METHODS: We used nationally representative adverse drug event data from the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project and national retail pharmacy prescription data from IMS Health to estimate the frequency and rates of emergency hospitalizations for unsupervised prescription medication ingestions by young children (2007-2011). RESULTS: On the basis of 1513 surveillance cases, 9490 estimated emergency hospitalizations (95% confidence interval: 6420-12,560) occurred annually in the United States for unsupervised prescription medication ingestions among children aged <6 years from 2007 through 2011; 75.4% involved 1- or 2-year old children. Opioids (17.6%) and benzodiazepines (10.1%) were the most commonly implicated medication classes. The most commonly implicated active ingredients were buprenorphine (7.7%) and clonidine (7.4%). The top 12 active ingredients, alone or in combination with others, were implicated in nearly half (45.0%) of hospitalizations. Accounting for the number of unique patients who received dispensed prescriptions, the hospitalization rate for unsupervised ingestion of buprenorphine products was significantly higher than rates for all other commonly implicated medications and 97-fold higher than the rate for oxycodone products (200.1 vs 2.1 hospitalizations per 100,000 unique patients). CONCLUSIONS: Focusing unsupervised ingestion prevention efforts on medications with the highest hospitalization rates may efficiently achieve large public health impact.

Use of antidiabetic drugs in the U.S., 2003-2012.

OBJECTIVE: To describe market trends for antidiabetic drugs, focusing on newly approved drugs, concomitant use of antidiabetic drugs, and effects of safety concerns and access restrictions on thiazolidinedione use. RESEARCH DESIGN AND METHODS: Nationally projected data on antidiabetic prescriptions for adults dispensed from U.S. retail pharmacies were extracted from IMS Health Vector One National and Total Patient Tracker for 2003-2012 and from Encuity Research Treatment Answers and Symphony Health Solutions PHAST Prescription Monthly for 2012. RESULTS: Since 2003, the number of adult antidiabetic drug users increased by 42.9% to 18.8 million in 2012. Metformin use increased by 97.0% to 60.4 million prescriptions dispensed in retail pharmacies in 2012. Among antidiabetic drugs newly approved for marketing between 2003 and 2012, the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin had the largest share with 10.5 million prescriptions in 2012. Rosiglitazone use plummeted to <13,000 prescriptions dispensed in retail or mail-order pharmacies in 2012. Concomitancy analyses showed that 44.9% of metformin use was for monotherapy. Between 33.4 and 48.1% of sulfonylurea, DPP-4 inhibitor, thiazolidinedione, and glucagon-like peptide 1 analog use was not accompanied by metformin. CONCLUSIONS: The antidiabetic drug market is characterized by steady increases in volume, and newly approved drugs experienced substantial uptake, especially DPP-4 inhibitors. The use of rosiglitazone has been negligible since restrictions were put in place in 2011. Further study is needed to understand why one-third to one-half of other noninsulin antidiabetic drug use was not concomitant with metformin use despite guidelines recommending that metformin be continued when other agents are added to treatment.

Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012.

Bisphosphonates have been widely prescribed to postmenopausal women for treatment and prevention of osteoporosis. Given a background of reports of recent safety problems, questions about optimal duration of use, and the patent expiration of Fosamax in February 2008, we accessed data from pharmaceutical marketing research databases to describe trends in dispensed prescriptions and sales of oral bisphosphonates, characteristics of patients and prescribers, and sales of intravenous bisphosphonates for osteoporosis treatment. An estimated 21.3million prescriptions for oral bisphosphonates were dispensed in U.S. retail pharmacies in 2002 that increased 46% to a peak of 31.0million in 2007 and 2008, and declined by 53% in a four year-period to 14.7million in 2012. Sales data (number of packages sold in all settings of care) showed parallel trends (66% increase from 2002 through 2007 and 51% decrease from 2007 through 2012). Similarly, intravenous bisphosphonate sales for osteoporosis treatment grew 3.8-fold from 149.5 thousand packages in 2007 to 561.6 thousand in 2010, followed by a 22% decrease in 2012. Data from an ongoing monthly office-based survey indicated physicians mentioned oral bisphosphonates primarily in visits of older aged Caucasian women with lower body mass for osteoporosis. Frequencies of oral bisphosphonate mentions increased between 2002 and 2012 in visits of Asians and for osteopenia diagnoses. These data indicate a substantial decline in prescriptions and sales of oral (since 2007-2008) and intravenous (since 2010) bisphosphonates for osteoporosis treatment in the United States. Reasons for, and implications of, the decline should be considered for future research.

Lower risk of Creutzfeldt-Jakob disease in pituitary growth hormone recipients initiating treatment after 1977.

CONTEXT: Creutzfeldt-Jakob disease (CJD) caused by contaminated cadaveric pituitary-derived human GH (hGH) has been responsible for hundreds of deaths worldwide. Studies of U.S. National Hormone and Pituitary Program (NHPP) hGH recipients have found CJD only in patients treated before 1977, when a new purification procedure with column chromatography was implemented for hGH extraction. OBJECTIVE: Our objective was to provide updated information on transmission of CJD to NHPP hGH recipients and determine whether recipients of hGH produced after 1977 had a significantly lower CJD risk than pre-1977 recipients. PATIENTS: A total of 5570 NHPP hGH recipients were included in the study: 2099 in the pre-1977 cohort and 3471 in the post-1977 cohort. MAIN OUTCOME MEASURE: We used probability distribution functions to determine whether the observed number of CJD cases in the post-1977 cohort was significantly fewer than expected if the CJD risk was equal to that of the pre-1977 cohort, controlling for treatment duration and follow-up time. RESULTS: All 22 CJD cases (diagnosed from 1984-2009) occurred in the pre-1977 hGH recipients. Almost half (47.9%) of pre-1977 recipients had a treatment duration of at least 5 yr compared with only 13.8% for post-1977 recipients. Based on the rates present in the pre-1977 cohort, the probability of observing no cases in the post-1977 cohort by chance alone was low (P = 0.0019). CONCLUSIONS: Risk of acquiring CJD was significantly lower for post-1977 NHPP hGH recipients than for pre-1977 recipients, suggesting that the new purification procedure in 1977 may have greatly reduced or eliminated CJD agent in hGH.

Use of parenteral iron products and serious anaphylactic-type reactions.

Controversy exists about the safety of the parenteral iron dextran products, Dexferrum and INFeD, which have been associated with rare, serious anaphylactic-type reactions. In the United States, their product labels carry boxed warnings of this adverse event; some have called for the withdrawal from marketing of the higher molecular weight Dexferrum. Between 2002 and 2007, sales of Dexferrum, INFeD, and iron gluconate Ferrlecit declined 32.5%, 21%, and 4.8%, respectively, while sales of iron sucrose Venofer increased 160%. Voluntary reports submitted to the Food and Drug Administration show anaphylactic reactions and symptoms for the four parenteral iron products. Because of underreporting, possible differential reporting, absence of iron dextran brand names, and incomplete use (denominator) data, incidence rates and relative risk estimates cannot be calculated. U.S. death certificate data show that for most years from 1979 through 2006, no more than 3 deaths per year were coded to "adverse events in therapeutic use of iron preparations;" brand names were not consistently recorded. Emergency department data show small numbers of visits for treatment of allergic reactions with intravenous iron preparations. The data presented herein show that allergic reactions are possible with all four parenteral iron products, and it is difficult to determine which product has the largest risk based on sales data, voluntarily submitted adverse event reports, death certificates, ED visits, and observational studies performed to date. To help differentiate risk among the parenteral iron products, the brand name of the product always should be provided on medical records, death certificates, and adverse drug reaction reports.

Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action.

BACKGROUND: Warfarin sodium is widely used and causes bleeding; a review might suggest the need for regulatory action by the US Food and Drug Administration (FDA). METHODS: We accessed warfarin prescriptions from the National Prescription Audit Plus database of IMS Health (Plymouth Meeting, Pennsylvania), adverse event reports submitted to the FDA, deaths due to therapeutic use of anticoagulants from vital statistics data, and warfarin bleeding complications from national hospital emergency department data. RESULTS: The number of dispensed outpatient prescriptions for warfarin increased 45%, from 21 million in 1998 to nearly 31 million in 2004. The FDA's Adverse Event Reporting System indicated that warfarin is among the top 10 drugs with the largest number of serious adverse event reports submitted during the 1990 and 2000 decades. From US death certificates, anticoagulants ranked first in 2003 and 2004 in the number of total mentions of deaths for drugs causing "adverse effects in therapeutic use." Data from hospital emergency departments for 1999 through 2003 indicated that warfarin was associated with about 29 000 visits for bleeding complications per year, and it was among the drugs with the most visits. These data are consistent with literature reports of major bleeding frequencies for warfarin as high as 10% to 16%. CONCLUSIONS: Use of warfarin has increased, and bleeding from warfarin use is a prevalent reaction and an important cause of mortality. Consequently, a "black box" warning about warfarin's bleeding risk was added to the US product labeling in 2006. Physicians and nurses should tell patients to immediately report signs and symptoms of bleeding. A Medication Guide, which is required to be provided with each prescription, reinforces this message.

Surveillance of prescription drug-related mortality using death certificate data.

BACKGROUND: The prescription drugs or drug classes that are most frequently associated with death in the US might be identifiable from death certificate data. OBJECTIVE: To identify the drugs/drug classes associated with the greatest numbers of deaths in the US that might be considered as possible targets for prevention. STUDY DESIGN: US vital statistics data were accessed in order to identify International Classification of Diseases (10th Revision) [ICD-10] codes indicating that prescription drugs had caused or contributed to death and diseases with significant drug-related mortality. MAIN OUTCOME MEASURE: ICD-10 codes for primarily prescription drugs that were listed as the underlying cause or as 'total mentions' on death certificates and were implicated in >or=1000 deaths in any one year were selected. The annual number of deaths by ICD-10 code was obtained from the Division of Vital Statistics, National Center for Health Statistics. Codes for diseases with significant drug-related aetiologies and involvement in >or=1000 deaths in any one year were also identified and analysed separately. RESULTS: For the selected ICD-10 codes, a total of 25 031 deaths were listed as having a prescription drug as the underlying cause in 2003, compared with 16 135 in 1999, a 55% increase. Total mentions of these codes increased from 46 523 in 1999 to 72 080 in 2003, also a 55% increase. Most codes involved 'poisonings' (overdose or the wrong substance given or taken in error that is accidental, intentional or with undetermined intent). Drugs associated with poisoning deaths had central nervous system effects. Among the codes associated with specified drug classes, poisonings and accidental poisonings involving narcotics, hallucinogens, psychoactive substances and opioids (other than opium and heroin) were associated with the largest numbers of deaths. Drug-related codes associated with the largest percentage increases in deaths between 1999 and 2003 included poisoning due to methadone (275%); poisoning by other and unspecified antidepressants (primarily selective serotonin reuptake inhibitors) [130%]; and poisoning by psychostimulants with potential for abuse (amfetamines and drugs for attention deficit hyperactivity disorder) [117%]. Anticoagulants were associated with the largest numbers of deaths with codes involving "adverse effects in therapeutic use". Among diseases with significant drug-related aetiologies, Clostridium difficile enterocolitis (associated primarily with antibacterials) had the largest percentage increase in total mentions, with a 203% rise between 1999 and 2003. CONCLUSIONS: Deaths due to overdoses are the most prominent cause of drug-related mortality in death certificate data. Certain drugs and drug classes, especially the opioids (e.g. narcotics, methadone), psychoactive drugs (e.g. antidepressants, amfetamines), anticoagulants and antibacterials (which cause or contribute to C. difficile enterocolitis) are associated with large and increasing numbers of deaths and preventive strategies should be considered.

Trends in outpatient prescription drug use and related costs in the US: 1998-2003.

OBJECTIVE: To present a brief synopsis of trends in the number of prescriptions and retail costs of outpatient drugs dispensed in the US between 1998 and 2003. METHODS: Data were extracted from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index databases. RESULTS: In 1998, 2.7 billion outpatient prescriptions were dispensed versus 3.6 billion in 2003. This equates to a 33.3% increase over the 6-year period. Of the top 20 most dispensed drugs by volume, 40% were launched in the 1990s or 2000s. Retail costs for the total market of dispensed outpatient prescription drugs were 96.1 billion US dollars in 1998 and 196 billion US dollars in 2003, a 104% increase. Of the top 20 most dispensed drugs by retail cost, all were tradename drugs and were launched in the 1990s or 2000s. CONCLUSIONS: These data indicate a large increase in the US over a short time period in dispensed outpatient prescriptions and their associated retail costs.

Deaths attributed to X-ray contrast media on U.S. death certificates.

OBJECTIVE: The objectives of our study were to determine the number, rate, and types of deaths attributed to specific X-ray contrast media on the basis of U.S. death certificates and to attempt to assess the comparative safety of commonly used diagnostic X-ray contrast agents using death certificate information. CONCLUSION: From 1999 through 2001, deaths attributed to the International Classification of Diseases (ICD) code for contrast media occurred at the rate of 1.1-1.2 per million contrast media packages distributed. An analysis of 1999 death certificates indicated that most deaths attributed to contrast media predictably were associated with renal failure or nephropathy and anaphylaxis or allergic reactions. Risk assessment of the comparative safety of classes or agents was limited by lack of specific contrast media names. Names of administered contrast agents should be recorded in patients' medical records and communicated to primary care physicians and certifiers of death in the event of serious sequelae after an identified recent radiologic procedure.

Adverse drug event surveillance and drug withdrawals in the United States, 1969-2002: the importance of reporting suspected reactions.

BACKGROUND: The Adverse Event Reporting System is the primary surveillance database used by the Food and Drug Administration for identifying postmarketing drug safety problems. METHODS: We analyzed all reports of suspected adverse drug reactions submitted to the Food and Drug Administration from the inception of the Adverse Event Reporting System database in 1969 through December 2002. We documented drug withdrawals and restricted distribution programs based on safety concerns. RESULTS: During the 33-year period from 1969 when adverse drug event reporting was initiated through 2002, about 2.3 million case reports of adverse events for the cumulative number of approximately 6000 marketed drugs were entered in the database. Most reports were for female patients. During this period, numerous drug reactions have been identified and added to the product labeling as boxed warnings, warnings, precautions, contraindications, and adverse reactions. More than 75 drugs/drug products have been removed from the market due to safety problems. In addition, 11 drugs have special requirements for prescriptions or have restricted distribution programs. Drugs withdrawn or restricted represent a small proportion (about 1%) of marketed drugs. CONCLUSIONS: The Food and Drug Administration's Adverse Event Reporting System is the primary surveillance database used for the identification of safety problems of marketed drugs. Despite the limitations of underreporting, differential reporting, and uneven quality, submitted reports often allow the identification of serious adverse events that are added to the product labeling information. In rare instances, additional regulations, up to and including market removal, have been required. We encourage physicians, pharmacists, other health care professionals, and patients to continue to report serious suspected and known adverse drug reactions to manufacturers and the Food and Drug Administration.

Use of menopausal hormones in the United States, 1992 through June, 2003.

PURPOSE: The Women's Health Initiative (WHI) study that documented an unfavorable benefit to risk ratio of Prempro and subsequently an increased risk of stroke with menopausal estrogen prompted us to investigate the use during 1992 through June 2003 of menopausal hormones in the United States. METHODS: Two pharmaceutical research databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index, were accessed and analyzed. RESULTS: The number of dispensed outpatient prescriptions for oral menopausal estrogens and oral combination estrogen-progestins increased 2.5-fold (153%) from 34.5 million dispensed in 1992 to a high of 87.3 million in 2000. For July 2002 through June 2003, the year following the publication of the results of the WHI trial, prescriptions for these products declined to 59.6 million, a 32% decrease from their peak in 2000. Prescriptions for transdermal estrogen and transdermal combination estrogen-progestin products increased from 5.2 million dispensed in 1992 to their peak of 8.3 million in 2000, and declined 10% to 7.5 million during July 2002 through June 2003. By contrast, prescriptions for oral menopausal progestins rose to 17.5 million in 1995 and then steadily declined. In the year after the WHI, prescriptions for oral progestins decreased 49% to 8.9 million from their peak in 1995. The earlier decline in oral progestin prescriptions was primarily due to the marketing in 1995 of the popular oral combination estrogen-progestin drugs. CONCLUSIONS: Prescriptions dispensed for menopausal hormones increased substantially between 1992 and peaked in 2000. By June 2003, prescriptions for oral menopausal estrogens and oral combination estrogen-progestins had declined by about one-third from their peak year.

Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients.

OBJECTIVE: Patients who received pituitary-derived growth hormone (GH) are at excess risk of mortality from Creutzfeldt-Jakob disease. We investigated whether they were at increased risk of death from other conditions, particularly preventable conditions. STUDY DESIGN: A cohort (N=6107) from known US pituitary-derived GH recipients (treated 1963-1985) was studied. Deaths were identified by reports from physicians and parents and the National Death Index. Rates were compared with the expected rates for the US population standardized for race, age, and sex. RESULTS: There were 433 deaths versus 114 expected (relative risk [RR], 3.8; 95% confidence interval [CI], 3.4-4.2; P<.0001) from 1963 through 1996. Risk was increased in subjects with GH deficiency caused by any tumor (RR, 10.4; 95% CI, 9.1-12.0; P<.0001). Surprisingly, subjects with hypoglycemia treated within the first 6 months of life were at extremely high risk (RR, 18.3; 95% CI, 9.2-32.8; P<.0001), as were all subjects with adrenal insufficiency (RR, 7.1; 95% CI, 6.2-8.2; P<.0001). A quarter of all deaths were sudden and unexpected. Of the 26 cases of Creutzfeldt-Jakob disease, four cases have died since 2000. CONCLUSIONS: The death rate in pituitary-derived GH recipients was almost four times the expected rate. Replacing pituitary-derived GH with recombinant GH has eliminated only the risk of Creutzfeldt-Jakob disease. Hypoglycemia and adrenal insufficiency accounted for far more mortality than Creutzfeldt-Jakob disease. The large number of potentially preventable deaths in patients with adrenal insufficiency and hypoglycemia underscores the importance of early intervention when infection occurs in patients with adrenal insufficiency, and aggressive treatment of panhypopituitarism.