Switching patterns of immediate-release forms of generic mixed amphetamine salts products among privately and publicly insured individuals aged 15-64 years in the United States, 2013-2019.

PURPOSE: Immediate-release forms of generic mixed amphetamine salts (MAS) have been the subject of passive surveillance reports signaling lack of effectiveness. We examined switching patterns that might suggest whether long-term users of specific MAS are more likely to switch away or switch back after use of the MAS of interest in the FDA's Sentinel Distributed Database. METHODS: We required at least 60-day continuous supply of selected MAS grouped by Abbreviated New Drug Application (ANDA) to describe patterns of switching away from and to generics approved under the ANDAs of interest among individuals ages 15-64 years with attention deficit hyperactivity disorder or narcolepsy during 2013-2019. RESULTS: We observed the greatest number of treatment episodes for ANDA 040422 (n = 525 771), followed by ANDA 202424 (n = 181 693), ANDA 040439 (n = 62 363), ANDA 040440 (n = 21 143), and ANDA 040480 (n = 8792). Of those with switches away from their original ANDA, episodes initiated on generic products under ANDA 040422 (48.6%) and ANDA 202424 (43.0%) were most likely to switch back, while those initiated on generic product under ANDA 040480 were least likely (24.1%). Of those episodes with switches to a generic under an ANDA of interest, about one-third (range 27.1% to 37.0%) switched back to the same product. These switches back had a median time to switch of about 30 days. CONCLUSIONS: These descriptive analyses, although subject to limitations, did not suggest increased switching away or switching back after use of the generics of interest. Continued post-marketing surveillance is warranted.

Prescription medication use and baseline health status of women with live-birth deliveries in a national data network.

BACKGROUND: The US Food and Drug Administration increasingly uses administrative databases to conduct surveillance of medications used during pregnancy. To assess adverse fetal effects, administrative records must be linked between the mother and infant. The Sentinel Initiative's Mother-Infant Linkage Table provides a large cohort of linked deliveries from national, regional, and public insurance claims in the United States for the US Food and Drug Administration to conduct surveillance. OBJECTIVE: This study aimed to describe baseline health conditions and prescription medication use during pregnancy in cohorts of women with a live-birth delivery linked and not linked to an infant. STUDY DESIGN: Live-birth deliveries in women aged 10 to 54 years with at least 391 days of medical and drug coverage before delivery were identified in the Sentinel Mother-Infant Linkage Table from 2000 to 2019. Two cohorts were created for analysis: deliveries linked to infant records (linked deliveries, n=2,320,805) and deliveries unable to be linked to an infant (not-linked deliveries, n=504,785). Baseline health conditions, pregnancy history, healthcare utilization, and pregnancy conditions were defined using International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, diagnosis and procedure codes. Medication exposure was identified in a 90-day prepregnancy period and in each trimester. RESULTS: Few notable differences were observed between the linked and not-linked deliveries except for maternal age and preterm birth; the not-linked cohort was 3.4 years younger on average and more likely to have a preterm delivery. At baseline among the linked deliveries, the most common conditions were depression and anxiety (5.2% each), acquired hypothyroidism (5.0%), pain conditions (3.9%), and asthma (2.8%). Among linked deliveries, 6.9% had evidence of gestational diabetes mellitus, 3.9% had gestational hypertension, and 4.5% had preeclampsia or eclampsia. The most commonly used medications during pregnancy in the linked deliveries were antibacterials (41.6%) and antiemetics (21.5%); similar medication use patterns were observed in the not-linked cohort. Age trends were observed for some medication groups; anti-infectives, pain medications, and antiemetics were more common in younger mothers, whereas endocrine medications were more common in older mothers. CONCLUSION: Similarities between the linked and not-linked cohorts suggested that the ability to link mother and infant records is not influenced by maternal health status. In the linked cohort, the prevalence of specific pregnancy complications and medication use were similar to previously reported national estimates. Some baseline comorbidities, such as obesity and smoking, may be underestimated in the Sentinel Mother-Infant Linkage.

A General Propensity Score for Signal Identification Using Tree-Based Scan Statistics.

The tree-based scan statistic (TreeScan; Martin Kulldorff, Harvard Medical School, Boston, Massachusetts) is a data-mining method that adjusts for multiple testing of correlated hypotheses when screening thousands of potential adverse events for signal identification. Simulation has demonstrated the promise of TreeScan with a propensity score (PS)-matched cohort design. However, it is unclear which variables to include in a PS for applied signal identification studies to simultaneously adjust for confounding across potential outcomes. We selected 4 pairs of medications with well-understood safety profiles. For each pair, we evaluated 5 candidate PSs with different combinations of 1) predefined general covariates (comorbidity, frailty, utilization), 2) empirically selected (data-driven) covariates, and 3) covariates tailored to the drug pair. For each pair, statistical alerting patterns were similar with alternative PSs (≤11 alerts in 7,996 outcomes scanned). Inclusion of covariates tailored to exposure did not appreciably affect screening results. Inclusion of empirically selected covariates can provide better proxy coverage for confounders but can also decrease statistical power. Unlike tailored covariates, empirical and predefined general covariates can be applied "out of the box" for signal identification. The choice of PS depends on the level of concern about residual confounding versus loss of power. Potential signals should be followed by pharmacoepidemiologic assessment where confounding control is tailored to the specific outcome(s) under investigation.

Pilot Study Comparing Adverse Cardiorespiratory Events among Pharmacologically and Nonpharmacologically Treated Infants Undergoing Monitoring for Neonatal Abstinence Syndrome.

There is variation in cardiorespiratory monitoring practices for neonatal abstinence syndrome. We examined the incidence of cardiorespiratory adverse events in infants with neonatal abstinence syndrome who were treated or nontreated pharmacologically. Eight (10%) in the nontreated and 23 (19%) in the treated group experienced adverse events. This warrants further investigation in a larger cohort.

Placental OPRM1 DNA methylation and associations with neonatal opioid withdrawal syndrome, a pilot study.

AIMS: Epigenetic variation of DNA methylation of the mu-opioid receptor gene (OPRM1) has been identified in the blood and saliva of individuals with opioid use disorder (OUD) and infants with neonatal opioid withdrawal syndrome (NOWS). It is unknown whether epigenetic variation in OPRM1 exists within placental tissue in women with OUD and whether it is associated with NOWS outcomes. In this pilot study, the authors aimed to 1) examine the association between placental OPRM1 DNA methylation levels and NOWS outcomes, and 2) compare OPRM1 methylation levels in opioid-exposed versus non-exposed control placentas. METHODS: Placental tissue was collected from eligible opioid (n = 64) and control (n = 29) women after delivery. Placental DNA was isolated and methylation levels at six cytosine-phosphate-guanine (CpG) sites within the OPRM1 promoter were quantified. Methylation levels were evaluated for associations with infant NOWS outcome measures: need for pharmacologic treatment, length of hospital stay (LOS), morphine treatment days, and treatment with two medications. Regression models were created and adjusted for clinical co-variates. Methylation levels between opioid and controls placentas were also compared. RESULTS: The primary opioid exposures were methadone and buprenorphine. Forty-nine (76.6%) of the opioid-exposed infants required pharmacologic treatment, 10 (15.6%) two medications, and average LOS for all opioid-exposed infants was 16.5 (standard deviation 9.7) days. There were no significant associations between OPRM1 DNA methylation levels in the six CpG sites and any NOWS outcome measures. No significant differences were found in methylation levels between the opioid and control samples. CONCLUSIONS: No significant associations were found between OPRM1 placental DNA methylation levels and NOWS severity in this pilot cohort. In addition, no significant differences were seen in OPRM1 methylation in opioid versus control placentas. Future association studies examining methylation levels on a genome-wide level are warranted.

Standard Fixed-Schedule Methadone Taper Versus Symptom-Triggered Methadone Approach for Treatment of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: We compared hospitalization outcomes in infants with neonatal opioid withdrawal syndrome (NOWS) treated with a novel symptom-triggered methadone approach (STMA) versus a fixed-schedule methadone taper (FSMT). METHODS: This was a single-center quality-improvement study of infants pharmacologically treated for NOWS. Outcomes were compared over time by using statistical process control charts and between the baseline FSMT (July 2016-November 2017) and intervention STMA (December 2017-May 2018) groups, including median hospital length of stay (LOS), methadone treatment days, total milligrams of methadone, and need for adjunctive agents. RESULTS: There were 48 infants in the FSMT group and 28 in the STMA group. Infants treated with STMA had a median LOS of 10.5 days (interquartile range [IQR] 10.5) versus 17.0 days (IQR 3.9; P = .003) in the FSMT group, with a 9.2-day difference in methadone treatment days (2.5 [IQR 9.0] vs 11.7 [IQR 4.0]; P = .0001), meeting criteria for statistical process control special cause variation. The average number of symptom-triggered doses was 2.1 (SD 1.0). Six infants in the STMA group were converted to FSMT after failing a trial of STMA. Infants successfully treated with the STMA (N = 22) had a median LOS of 10.0 days (IQR 4.0) compared with 17.0 (IQR 3.9) in the baseline FSMT group (P < .0001). CONCLUSIONS: STMA was associated with a significant reduction in median LOS and amount of methadone treatment. A symptom-triggered approach to NOWS may reduce LOS and medication exposure.