Trends in Incident Prescriptions for Behavioral Health Medications in the US, 2018-2022.

Importance: The COVID-19 pandemic reportedly increased behavioral health needs and impacted treatment access. Objective: To assess changes in incident prescriptions dispensed for medications commonly used to treat depression, anxiety, attention-deficit/hyperactivity disorder (ADHD), and opioid use disorder (OUD), before and during the COVID-19 pandemic. Design, Setting, and Participants: This was a cross-sectional study using comprehensive, population-level, nationally projected data from IQVIA National Prescription Audit on incident prescriptions (prescriptions dispensed to patients with no prior dispensing from the same drug class in the previous 12 months) dispensed for antidepressants, benzodiazepines, Schedule II (C-II) stimulants, nonstimulant medications for ADHD, and buprenorphine-containing medication for OUD (MOUD), from US outpatient pharmacies. Data were analyzed from April 2018 to March 2022. Exposure: Incident prescriptions by drug class (by prescriber specialty, patient age, and sex) and drug. Main Outcomes and Measures: Interrupted time-series analysis to compare changes in trends in the monthly incident prescriptions dispensed by drug class and percentage changes in aggregate incident prescriptions dispensed between April 2018 and March 2022. Results: Incident prescriptions dispensed for the 5 drug classes changed from 51 500 321 before the COVID-19 pandemic to 54 000 169 during the pandemic. The largest unadjusted percentage increase in incident prescriptions by prescriber specialty was among nurse practitioners across all drug classes ranging from 7% (from 1 811 376 to 1 944 852; benzodiazepines) to 78% (from 157 578 to 280 925; buprenorphine MOUD), whereas for patient age and sex, the largest increases were within C-II stimulants and nonstimulant ADHD drugs among patients aged 20 to 39 years (30% [from 1 887 017 to 2 455 706] and 81% [from 255 053 to 461 017], respectively) and female patients (25% [from 2 352 095 to 2 942 604] and 59% [from 395 678 to 630 678], respectively). Trends for C-II stimulants and nonstimulant ADHD drugs (slope change: 4007 prescriptions per month; 95% CI, 1592-6422 and 1120 prescriptions per month; 95% CI, 706-1533, respectively) significantly changed during the pandemic, exceeding prepandemic trends after an initial drop at the onset of the pandemic (level changes: -50 044 prescriptions; 95% CI, -80 202 to -19 886 and -12 876 prescriptions; 95% CI, -17 756 to -7996, respectively). Although buprenorphine MOUD dropped significantly (level change: -2915 prescriptions; 95% CI, -5513 to -318), trends did not significantly change for buprenorphine MOUD, antidepressants, or benzodiazepines. Conclusions and Relevance: Incident use of many behavioral health medications remained relatively stable during the COVID-19 pandemic in the US, whereas ADHD medications, notably C-II stimulants, sharply increased. Additional research is needed to differentiate increases due to unmet need vs overprescribing, highlighting the need for further ADHD guideline development to define treatment appropriateness.

The impact of hydrocodone rescheduling on utilization, abuse, misuse, and overdose deaths.

PURPOSE: To evaluate the impact of increased federal restrictions on hydrocodone combination product (HCP) utilization, misuse, abuse, and overdose death. METHODS: We assessed utilization, misuse, abuse, and overdose death trends involving hydrocodone versus select opioid analgesics (OAs) and heroin using descriptive and interrupted time-series (ITS) analyses during the nine quarters before and after the October 2014 rescheduling of HCPs from a less restrictive (CIII) to more restrictive (CII) category. RESULTS: Hydrocodone dispensing declined >30% over the study period, and declines accelerated after rescheduling. ITS analyses showed that immediately postrescheduling, quarterly hydrocodone dispensing decreased by 177M dosage units while codeine, oxycodone, and morphine dispensing increased by 49M, 62M, and 4M dosage units, respectively. Postrescheduling, hydrocodone-involved misuse/abuse poison center (PC) case rates had a statistically significant immediate drop but a deceleration of preperiod declines. There were small level increases in codeine-involved PC misuse/abuse and overdose death rates immediately after HCP's rescheduling, but these were smaller than level decreases in rates for hydrocodone. Heroin-involved PC case rates and overdose death rates increased across the study period, with exponential increases in PC case rates beginning 2015. CONCLUSIONS: HCP rescheduling was associated with accelerated declines in hydrocodone dispensing, only partially offset by smaller increases in codeine, oxycodone, and morphine dispensing. The net impact on hydrocodone and other OA-involved misuse/abuse and fatal overdose was unclear. We did not detect an immediate impact on heroin abuse or overdose death rates; however, the dynamic nature of the crisis and data limitations present challenges to causal inference.

Repeated or Continuous Medically Supervised Ketamine Administration Associated with Hepatobiliary Adverse Events: A Retrospective Case Series.

INTRODUCTION: Emerging off-label medical uses of ketamine for the treatment of persistent conditions such as depression and chronic pain often require repeated administration. Cases reported by other countries suggest that long-term and repeated exposure to ketamine may be associated with several risks, including but not limited to hepatobiliary damage. OBJECTIVE: We aimed (1) to characterize the association between repeated administration of ketamine for off-label medical use and hepatobiliary events and (2) to describe recent trends in the use of ketamine across different clinical settings. METHODS: We conducted a retrospective case series analysis, utilizing reports identified from the US Food and Drug Administration Adverse Event Reporting System database as well as the medical literature. We included all cases reported through July 2018 describing both repeated exposure to ketamine in a hospital or ambulatory setting and a hepatobiliary adverse event. We excluded cases describing ketamine abuse. We identified adverse hepatobiliary events using the Medical Dictionary for Regulatory Activities (MedDRA®) and summarized various case characteristics including: patient demographics, route of ketamine administration, dose, time to onset of event, type of event, and pre-existing risk factors for hepatobiliary disease. To assess trends in the demand for ketamine, we used IQVIA, National Sales Perspectives™ to provide the nationally estimated number of vials sold for ketamine from the manufacturer to all US channels of distribution from 2013 through 2017. RESULTS: We identified 14 unique cases that met selection criteria with 21 hepatobiliary adverse events including liver enzyme elevation in all cases, biliary dilation with liver cirrhosis (n = 1), biliary dilation with cholangitis (n = 1), and pericholeductal fibrosis (n = 1). Most cases received ketamine for the treatment of complex regional pain syndrome or chronic pain. In cases with a reported time to onset, the majority of events occurred within 4 days. The nationally estimated number of ketamine vials sold in the USA from manufacturers to various channels of distribution increased from 1.2 million in 2013 to 2.1 million in 2017. CONCLUSIONS: We report an association between repeated or continuous administration of ketamine and hepatobiliary adverse events. Increased awareness among clinicians may mitigate these adverse outcomes, especially in the context of growing ketamine sales.

Food and Drug Administration Beyond the 2001 Government Accountability Office Report: Promoting Drug Safety for Women.

A 2001 U.S. Government Accountability Office (GAO) report indicated 8 of 10 drugs withdrawn from the U.S. market between 1997 and 2000 posed greater risk to women than men. We examined drugs withdrawn from the market for safety-related reasons from January 1, 2001, to January 1, 2018. To be included, drugs must be listed as discontinued on Drugs@FDA and either listed in the Federal Register or cited in literature as being withdrawn for safety-related reasons. Biologics, over-the-counter products, and medical devices were excluded. During the 17-year time span, 19 drugs were withdrawn from the market for safety-related reasons, fewer drugs per year compared to the 3-year period examined in the GAO report. Food and Drug Administration (FDA) has not recommended the market removal of any drug approved since 2005 due to the time from the start of the Q wave to the end of the T wave (QT) interval prolongation resulting in torsades de pointes (TdP) or other abnormal heart rhythms. Furthermore, no drugs approved after the implementation of FDA's 2009 guidance on drug-induced liver injury (DILI) have been withdrawn because of hepatoxicity. All, but one of the drugs discontinued from the market for safety-related reasons during the period examined were approved between 1957 and 2002. TdP and DILI are two relevant examples of drug-induced adverse events posing greater risk to women than men. FDA has made measurable progress incorporating consideration of sex and gender differences into drug trial development and FDA review of these data, supporting inclusion of women in clinical trials, providing a comprehensive drug safety review, and advancing postmarket surveillance and risk assessment, thus strengthening FDA's ability to protect public health.

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive-age women in the United States.

PURPOSE: To assess the prevalence and potential indications of PDE5 inhibitor use among pregnant and reproductive-age women in the United States. METHODS: We identified women 15 to 50 years with a livebirth from January 2001 through March 2018 in Sentinel Database. We assessed the prevalence of PDE5 inhibitor use prior to and during pregnancy by trimester, identified potential on- and off-label indications using predefined diagnosis codes recorded within 90 days before the estimated last menstrual period through delivery. Separately, we used data from IQVIA's National Prescription Audit and Total Patient Tracker to estimate the dispensed prescriptions for PDE5 inhibitors and the number of patients with PDE5 inhibitor prescriptions. RESULTS: We identified approximately 3.3 million pregnancies during 2001 to 2018, 96 of which had PDE5 inhibitor use during pregnancy. Prevalence of PDE5 inhibitor use was 2.61, 0.62, and 0.62 per 100, 000 live-born pregnancies during the first, second, or third trimesters, respectively. Among women exposed to a PDE5 inhibitor from 90 days before conception to the end of pregnancy, 25.0%, 31.1%, and 15.5% had a diagnosis code for fetal growth restriction, preeclampsia, and pulmonary arterial hypertension. In IQVIA data, an estimated 223, 000 prescriptions from July 2015 through June 2018 and 58, 000 women received prescriptions for PDE5 inhibitors in 2017, of whom approximately 15, 000 (26%) were aged 15 to 50 years. CONCLUSION: We found a low prevalence of PDE5 inhibitor use in pregnant and reproductive-age women. Given the very low prevalence of use and the inconsistency of neonatal mortality data across STRIDER centers, the risk to public health is low at present.

Patterns of opioid analgesic use in the U.S., 2009 to 2018.

ABSTRACT: Although overall outpatient dispensing of opioid analgesic prescriptions has declined, there may still be overprescribing. Understanding how many opioid analgesic units, primarily tablets, are dispensed with the intention of shorter-vs longer-term use can inform public health interventions. We used pharmacy prescription data to estimate the number of opioid analgesic tablets dispensed annually in the U.S. We studied patterns of new use of opioid analgesics by evaluating how many opioid analgesic prescriptions and tablets were dispensed to patients with no opioid analgesic prescriptions in the previous year. Estimated opioid analgesic tablets dispensed declined from a peak of 17.8 billion in 2012 to 11.1 billion in 2018. Patients newly starting opioid analgesics declined from 47.4 million patients in 2011 to 37.1 million patients in 2017. Approximately 40% fewer tablets were dispensed within a year to patients starting in 2017 (2.4 billion) compared with 2011 (4.0 billion). In 2011, patients with ≥5 opioid analgesic prescriptions within a year were dispensed 2.2 billion tablets (55% of all tablets in our study). This declined by 52% to 1.1 billion tablets (44% of all tablets) in 2017. Tablets dispensed within a year to patients with <5 opioid analgesic prescriptions declined by 26% from 2011 to 2017. Patients with ≥5 prescriptions comprised a small and decreasing proportion of all patients newly starting therapy. However, these patients received almost half of all tablets dispensed within a year to patients in our study, despite a larger decline than tablets dispensed to patients with <5 prescriptions within a year.

Trends and economic drivers for United States naloxone pricing, January 2006 to February 2017.

Anecdotal evidence indicates that naloxone prices have risen in recent years, but limited research has examined the magnitude of these increases and potential causes. We contribute nationally representative evidence to help answer each of these questions, including wholesale pricing data from a proprietary drug sales database spanning January 2006 to February 2017. We find that all formulations of naloxone increased in price since 2006 except for Narcan Nasal Spray. These cumulative increases totaled 2281% for the 0.4 MG single-dose products, 244% for the 2 MG single-dose products, 3797% for the 4 MG multi-dose products, and 469% for the 0.4 MG Evzio auto-injector. We believe that increased demand for naloxone from the opioid epidemic may explain the more gradual price increases for the 0.4 MG single-dose and 4 MG multi-dose products prior to 2012. On the other hand, we believe that the sudden, sustained prices increases occurring for all of the products since 2012 may be the result of a drug shortage for the 0.4 MG single-dose products and the fact that each naloxone product has historically been sold by only a single competitor.

Use of Proprietary Names by Prescribers for Generic Products.

BACKGROUND: Proprietary names are often used when prescribing drug products in the United States. The purpose of this study is to describe prescribers' use of proprietary names for generic products, branded-generic names, on prescription orders and to identify prescribing practice trends to inform the development and evaluation of new proprietary names. METHODS: To identify Abbreviated New Drug Application (ANDA) with branded-generic names approved between January 2003 and December 2012, we utilized the database provided by the FDA Office of Communications, Drugs@FDA . A national outpatient retail prescription database, IMS's Vector One: National (VONA) was used to identify prescribing trends by examining data for branded-generic names identified in Drugs@FDA as they were written on prescriptions for years 2003 to 2012, the last year of data collection for VONA. IMS Health, IMS National Sales Perspectives (IMS NSP) was used to retrieve the date that product sales were first reported (launch date). RESULTS: Our search of Drugs@FDA identified 65 distinct branded-generic names approved between January 2003 and December 2012. Data show that most of these products with branded-generic names are written on prescriptions and sold to pharmacies within a year of FDA approval. In some cases, the use of branded-generic names persists for up to 9 years after drug approval. CONCLUSION: This descriptive study confirmed that branded-generic names are used in prescribing. Thus, evaluation of orthographic and phonetic similarities between proposed proprietary names and branded-generic names is necessary when formulating and evaluating new proprietary names.

New Opioid Analgesic Approvals and Outpatient Utilization of Opioid Analgesics in the United States, 1997 through 2015.

BACKGROUND: The opioid epidemic, driven in part by increased prescribing, is a public health emergency. This study examines dispensed prescription patterns and approvals of new opioid analgesic products to investigate whether the introduction of these new drugs increases prescribing. METHODS: Prescribing patterns based on dispensed prescription claims from the U.S. retail setting were assessed with new brand and generic opioid analgesic products approved in the United States from 1997 through 2015. RESULTS: From 1997 through 2015, the U.S. Food and Drug Administration (Silver Spring, Maryland) approved 263 opioid analgesic products, including 33 brand products. Dispensed prescriptions initially increased 80% from 145 million prescriptions in 1997 to a peak of 260 million prescriptions in 2012 before decreasing by 12% to 228 million prescriptions in 2015. Morphine milligram equivalents dispensed per prescription increased from 486 in 1997 to a peak of 950 in 2010, before decreasing to 905 in 2015. In 2015, generic products accounted for 96% (218/228 million prescriptions) of all opioid analgesic prescriptions dispensed. The remaining prescriptions were dispensed for brand products, of which nearly half were dispensed for one brand product (OxyContin, Purdue, USA). CONCLUSIONS: There has been a dramatic increase in prescriptions dispensed for opioid analgesics since 1997 and an increasing number of opioid analgesic approvals; however, the number of prescriptions dispensed has declined since 2012 despite an increasing number of approvals. Examination of dispensed prescriptions shows a shifting and complex market where multiple factors likely influence prescribing; the approval of new products alone may not be sufficient to be a primary driver of increased prescribing. VISUAL ABSTRACT: An online visual overview is available for this article at http://links.lww.com/ALN/B705.

Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy.

BACKGROUND: Besides vaccines and otitis media medicines, most products prescribed for children have not been studied in the pediatric population. To remedy this, Congress enacted legislation in 1997, known as pediatric exclusivity (PE), which provides 6 months of additional market protection to drug sponsors in exchange for studying their products in children. METHODS: We reviewed requests for pediatric studies and subsequent labeling for drugs granted PE from 1998 through 2012. Regression analysis estimates the probability of demonstrating efficacy in PE trials. Variables include therapeutic group, year of exclusivity, product sales, initiation process, and small disease population. RESULTS: From 1998 through 2012, the US Food and Drug Administration issued 401 pediatric study requests. For 189 drugs, studies were completed and granted exclusivity. A total of 173 drugs (92%) received new pediatric labeling, with 108 (57%) receiving a new or expanded pediatric indication. Three drugs had non-efficacy trials. Efficacy was not established for 78 drugs. Oncology, cardiovascular, and endocrine drugs were less likely to demonstrate efficacy (P < .01) compared with gastrointestinal and pain/anesthesia drugs. Drugs studied later in the program were less likely to demonstrate efficacy (P < .05). Sales, initiation process, and small disease population were not significant predictors. CONCLUSIONS: Most drugs (173; 92%) granted exclusivity added pediatric information to their labeling as a result of PE, with 108 (57%) receiving a new or expanded pediatric indication. Therapeutic area and year of exclusivity influenced the likelihood of obtaining a pediatric indication. Positive and negative outcomes continue to inform the construct of future pediatric trials.

Trends of outpatient prescription drug utilization in US children, 2002-2010.

OBJECTIVE: To describe trends in outpatient prescription drug utilization in US children and the changes in major areas of pediatric therapeutic use for the years 2002 through 2010. METHODS: Large prescription databases (the IMS Vector One: National and Total Patient Tracker) were used to examine national drug utilization patterns for the US pediatric population (ages 0-17 years) from 2002 through 2010. RESULTS: In 2010, a total of 263.6 million prescriptions were dispensed to the US pediatric population, 7% lower than in 2002, while prescriptions dispensed to the adult population increased 22% during the same time. Analysis of pediatric drug utilization trends for the top 12 therapeutic areas in 2010 compared with 2002 showed decreases in systemic antibiotics (-14%), allergies (-61%), pain (-14%), depression (-5%), and cough/cold without expectorant (-42%) prescriptions, whereas asthma (14%), attention-deficit/hyperactivity disorder (46%), and contraceptive (93%) prescriptions increased. In 2010, amoxicillin was the most frequently dispensed prescription in infants (aged 0-23 months) and children (aged 2-11 years). Methylphenidate was the top prescription dispensed to adolescents (aged 12-17 years). Off-label use was identified, particularly for lansoprazole; ~358,000 prescriptions were dispensed in 2010 for infants <1 year old. CONCLUSIONS: Changes in the patterns of pediatric drug utilization were observed from 2002 to 2010. Changes include a decrease in antibiotic use and an increase in attention-deficit/hyperactivity disorder medication use during the examined time. This article provides an overview of pediatric outpatient drug utilization, which could set the stage for further in-depth analyses.