Opportunities for Pharmacogenetic Testing to Guide Dosing of Medications in Youths With Medicaid.

Importance: There are an increasing number of medications with a high level of evidence for pharmacogenetic-guided dosing (PGx drugs). Knowledge of the prevalence of dispensings of PGx drugs and their associated genes may allow hospitals and clinical laboratories to determine which pharmacogenetic tests to implement. Objectives: To investigate the prevalence of outpatient dispensings of PGx drugs among Medicaid-insured youths, determine genes most frequently associated with PGx drug dispenses, and describe characteristics of youths who were dispensed at least 1 PGx drug. Design, Setting, and Participants: This serial cross-sectional study includes data from 2011 to 2019 among youths aged 0 to 17 years in the Marketscan Medicaid database. Data were analyzed from August to December 2022. Main Outcomes and Measures: PGx drugs were defined as any medication with level A evidence as determined by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The number of unique youths dispensed each PGx drug in each year was determined. PGx drugs were grouped by their associated genes for which there was CPIC level A evidence to guide dosing, and a dispensing rate (No. of PGx drugs/100 000 youths) was determined for each group for the year 2019. Demographics were compared between youths dispensed at least 1 PGx drug and those not dispensed any PGx drugs. Results: The number of Medicaid-insured youths queried ranged by year from 2 078 683 youths in 2011 to 4 641 494 youths in 2017, including 4 126 349 youths (median [IQR] age, 9 [5-13] years; 2 129 926 males [51.6%]) in 2019. The proportion of Medicaid-insured youths dispensed PGx drugs increased from 289 709 youths (13.9%; 95% CI, 13.8%-14.0%) in 2011 to 740 072 youths (17.9%; 95% CI, 17.9%-18.0%) in 2019. Genes associated with the most frequently dispensed medications were CYP2C9, CYP2D6, and CYP2C19 (9197.0 drugs [95% CI, 9167.7-9226.3 drugs], 8731.5 drugs [95% CI, 8702.5-8759.5 drugs], and 3426.8 drugs [95% CI, 3408.1-3443.9 drugs] per 100 000 youths, respectively). There was a higher percentage of youths with at least 1 chronic medical condition among youths dispensed at least 1 PGx drug (510 445 youths [69.0%; 95% CI, 68.8%-69.1%]) than among 3 386 277 youths dispensed no PGx drug (1 381 544 youths [40.8%; 95% CI, 40.7%-40.9%) (P < .001) in 2019. Conclusions and Relevance: In this study, there was an increasing prevalence of dispensings for PGx drugs. This finding suggests that pharmacogenetic testing of specific drug-gene pairs should be considered for frequently prescribed PGx drugs and their implicated genes.

Cholic acid increases plasma cholesterol in Smith-Lemli-Opitz syndrome: A pilot study.

Background: Smith-Lemli-Opitz syndrome (SLOS) is an inherited disorder of cholesterol biosynthesis associated with congenital malformations, growth delay, intellectual disability and behavior problems. SLOS is caused by bi-allelic mutations in DHCR7, which lead to reduced activity of 7-dehydrocholesterol reductase that catalyzes the last step in cholesterol biosynthesis. Symptoms of SLOS are thought to be due to cholesterol deficiency and accumulation of its precursor 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC), and toxic oxysterols. Therapy for SLOS often includes dietary cholesterol supplementation, but lipids are poorly absorbed from the diet, possibly due to impaired bile acid synthesis. We hypothesized that bile acid supplementation with cholic acid would improve dietary cholesterol absorption and raise plasma cholesterol levels. Methods: Twelve SLOS subjects (10 M, 2F, ages 2-27 years) who had plasma cholesterol ≤125 mg/dL were treated with cholic acid (10 mg/kg/day) divided twice daily for 2 months. Plasma cholesterol, 7-DHC and 8-DHC were measured by GC-MS. Oxysterols were measured by ultra-high-performance LC-MS/MS. Data were analyzed using paired t-tests. Results: At baseline, plasma cholesterol was 75 ± 24 mg/dL (mean ± SD; range 43-125, n = 12). After 2 months on cholic acid, mean plasma cholesterol increased to 97 ± 29 mg/dL (p = 0.011). Eleven of 12 subjects showed an increase in plasma cholesterol that varied from 3.8% to 85.7% (mean 38.7 ± 23.3%). 7-Hydroxycholesterol decreased by 20.6% on average (p = 0.013) but no significant changes were seen in 7-DHC or 8-DHC. Mean body weight tended to increase (3.6% p = 0.069). Subjects tolerated cholic acid well and experienced no drug-related adverse events. Conclusions: In this pilot study, cholic acid supplementation was well tolerated and safe and resulted in an increase in plasma cholesterol in most SLOS subjects. Further controlled longitudinal studies are needed to look for the sustainability of the biochemical effect and possible clinical benefits.

A coordinated approach for managing polypharmacy among children with medical complexity: rationale and design of the Pediatric Medication Therapy Management (pMTM) randomized controlled trial.

BACKGROUND: Children with medical complexity (CMC) often rely upon the use of multiple medications to sustain quality of life and control substantial symptom burden. Pediatric polypharmacy (≥ 5 concurrent medications) is prevalent and increases the risk of medication-related problems (MRPs). Although MRPs are associated with pediatric morbidity and healthcare utilization, polypharmacy is infrequently assessed during routine clinical care for CMC. The aim of this randomized controlled trial is to determine if a structured pharmacist-led Pediatric Medication Therapy Management (pMTM) intervention reduces MRP counts, as well as the secondary outcomes of symptom burden and acute healthcare utilization. METHODS: This is a hybrid type 2 randomized controlled trial assessing the effectiveness of pMTM compared to usual care in a large, patient-centered medical home for CMC. Eligible patients include all children ages 2-18 years old, with ≥ 1 complex chronic condition, and with ≥ 5 active medications, as well as their English-speaking primary caregivers. Child participants and their primary parental caregivers will be randomized to pMTM or usual care before a non-acute primary care visit and followed for 90 days. Using generalized linear models, the overall effectiveness of the intervention will be evaluated using total MRP counts at 90 days following pMTM intervention or usual care visit. Following attrition, a total of 296 CMC will contribute measurements at 90 days, which provides > 90% power to detect a clinically significant 1.0 reduction in total MRPs with an alpha level of 0.05. Secondary outcomes include Parent-Reported Outcomes of Symptoms (PRO-Sx) symptom burden scores and acute healthcare visit counts. Program replication costs will be assessed using time-driven activity-based scoring. DISCUSSION: This pMTM trial aims to test hypotheses that a patient-centered medication optimization intervention delivered by pediatric pharmacists will result in lower MRP counts, stable or improved symptom burdens, and fewer cumulative acute healthcare encounters at 90 days following pMTM compared to usual care. The results of this trial will be used to quantify medication-related outcomes, safety, and value for a high-utilization group of CMC, and outcomes may elucidate the role of integrated pharmacist services as a key component of outpatient complex care programs for this priority pediatric population. TRIAL REGISTRATION: This trial was prospectively registered at clinicaltrials.gov (NCT05761847) on Feb 25, 2023.

Anticholinergic Medications and Parent-Reported Anticholinergic Symptoms in Neurologically Impaired Children.

CONTEXT: Children with severe neurological impairment and polypharmacy are exposed to anticholinergic (AC) medications that may have anticholinergic side effects, but this is understudied. Anticholinergic Cognitive Burden (ACB) scores measure total anticholinergic burden for a medication regimen, and scores ≥3 have been associated with increased morbidity and mortality in adults. OBJECTIVE: We assessed the relationship between ACB scores and parent-reported anticholinergic symptoms in children. METHODS: Cross-sectional study of patients one to 18 years-old with ICD-defined severe neurological impairment and polypharmacy. At routine clinical visits, total ACB scores were computed for all medications. Parent-reported AC symptoms (constipation, drowsiness, difficulty concentrating, dry mouth, or urinary problems) were assessed. Multivariable logistic regression was used to test the association between total ACB scores ≥3 for scheduled medications and the presence of AC symptoms, adjusted for age and recent acute healthcare utilization. RESULTS: Among 123 unique patients, 87% were prescribed AC medications. Common AC medication classes included: systemic antihistamines (64%), anxiolytics (53%), antidepressants (30%), H2 blockers (22%), and muscle relaxants (20%). Total ACB scores ≥3 were observed in 44% for scheduled medications and in 63% of patients for scheduled plus PRN medications. Total ACB scores ≥3 were significantly associated with an increased odds of ≥1 anticholinergic symptoms for scheduled medications (OR: 3.1; 95% CI: 1.4, 6.7) and for scheduled plus PRN medications (OR: 2.9; 95% CI: 1.3, 6.4). CONCLUSION: If replicated in larger populations, the association between elevated total ACB scores and anticholinergic side effects in children should prompt clinicians to consider deprescribing potentially unneeded anticholinergic medications.

Treatment-Refractory Dravet Syndrome: Considerations for Novel Medications.

Before 2018, there were no U.S. Food and Drug Administration-approved medications for managing seizures in Dravet syndrome (DS). Common agents used in the antiepileptic drug regimens of patients with DS included clobazam, valproic acid, topiramate, and levetiracetam, among others; however, these agents alone rarely provide adequate seizure control. Management of seizures in DS changed in recent years with the approval of cannabidiol and stiripentol in 2018 and fenfluramine in 2020. This continuing education article summarizes available efficacy and safety data involving cannabidiol, stiripentol, and fenfluramine and provides a practical review of dosing strategies, pharmacokinetics, and monitoring interventions relevant to their use.

Identifying opportunities for pediatric medication therapy management in children with medical complexity.

BACKGROUND: Despite potential benefits of medication therapy management (MTM) for complex pediatric patients, implementation of pediatric MTM services is rare. OBJECTIVES: To describe how a standardized pediatric MTM model identifies potential interventions and their impact on medication regimen complexity index (MRCI) scores in children with medical complexity (CMC) and polypharmacy. METHODS: This retrospective proof-of-concept study included pediatric patients receiving primary care in a large outpatient primary care medical home for CMC within a tertiary freestanding children's hospital from August 2020 to July 2021. Medication profiles of established patients aged 0-18 years with at least 5 active medications at the time of the index visit were assessed for medication-related concerns, potential interventions, and potential impact of proposed interventions on MRCI scores. RESULTS: Among 100 patients, an average of 3.4 ± 2.6 medication-related concerns was identified using the pediatric MTM model. Common medication-related concerns (>25% of patients) included inappropriate or unnecessary therapy, suboptimal therapy, undertreated symptom, adverse effect, clinically impactful drug-drug interaction, or duplication of therapy. A total of 97% had opportunities for 5.0 ± 2.9 potential interventions. Most common proposed interventions included drug discontinuation trial (69%), patient or caregiver education (55%), dosage form modification (51%), dose modification (49%), and frequency modification (46%). The mean baseline MRCI score was 32.6 (95% CI 29.3-35.8) among all patients. MRCI scores decreased by a mean of 4.9 (95% CI 3.8-5.9) after application of the theoretical interventions (P < 0.001). Mean potential score reduction was not significantly affected by patient age or number of complex chronic conditions. Potential impact of the proposed interventions on MRCI score was significantly greater in patients with higher baseline medication counts (P < 0.001). CONCLUSION: Most CMC would likely benefit from a pharmacist-guided pediatric MTM service. A standardized review of active medication regimens identified multiple medication-related concerns and potential interventions for nearly all patients. Proposed medication interventions would significantly reduce medication regimen complexity as measured by MRCI. Further prospective evaluation of a pharmacist-guided pediatric MTM service is warranted.

Allowable room temperature excursions for refrigerated medications: A 20-year review.

PURPOSE: The aim of this review was to build upon previous literature describing the maximum duration for which refrigerated medications can tolerate room temperature excursions while maintaining stability and potency. METHODS: During a 12-month period ending in June 2021, the prescribing information and published monographs from multiple pharmacy compendia were reviewed for all medications and biologic products approved by the US Food and Drug Administration (FDA) for human use since January 2000. Products that were subsequently withdrawn from the US market were excluded. When temperature excursion data was unavailable in published form, product manufacturers were surveyed via telephone and/or email. Acceptable storage information for all products for which storage is recommended at temperatures below room temperature (20-25 °C [68-77 °F]) was compiled and arranged in tabular format. RESULTS: Of the 705 products or formulations approved by FDA during the predefined time period, 246 were identified as requiring storage at temperatures below room temperature. After review of available prescribing information and manufacturer communications, if applicable, acceptable periods of excursion to temperatures at room temperature or higher were identified for 214 products (87%). CONCLUSION: Information related to acceptable periods of room temperature excursion was compiled for a total of 214 products approved for US distribution since 2000. The included tables may increase patient safety and decrease medication loss or related expenditures.

Complexity of Medication Regimens for Children With Neurological Impairment.

Importance: Parents of children with severe neurological impairment (SNI) manage complex medication regimens (CMRs) at home, and clinicians can help support parents and simplify CMRs. Objective: To measure the complexity and potentially modifiable aspects of CMRs using the Medication Regimen Complexity Index (MRCI) and to examine the association between MRCI scores and subsequent acute visits. Design, Setting, and Participants: This cross-sectional study was conducted between April 1, 2019, and December 31, 2020, at a single-center, large, hospital-based, complex care clinic. Participants were children with SNI aged 1 to 18 years and 5 or more prescribed medications. Exposure: Home medication regimen complexity was assessed using MRCI scores. The total MRCI score is composed of 3 subscores (dosage form, dose frequency, and specialized instructions). Main Outcomes and Measures: Patient-level counts of subscore characteristics and additional safety variables (total doses per day, high-alert medications, and potential drug-drug interactions) were analyzed by MRCI score groups (low, medium, and high score tertiles). Associations between MRCI score groups and acute visits were tested using Poisson regression, adjusted for age, complex chronic conditions, and recent health care use. Results: Of 123 patients, 73 (59.3%) were male with a median (interquartile range [IQR]) age of 9 (5-13) years. The median (IQR) MRCI scores were 46 (35-61 [range, 8-139]) overall, 29 (24-35) for the low MRCI group, 46 (42-50) for the medium MRCI group, and 69 (61-78) for the high MRCI group. The median (IQR) counts for the subscores were 6 (4-7) dosage forms per patient, 7 (5-9) dose frequencies per patient, and 5 (4-8) instructions per patient, with counts increasing significantly across higher MRCI groups. Similar trends occurred for total daily doses (median [IQR], 31 [20-45] doses), high-alert medications (median [IQR], 3 [1-5] medications), and potential drug-drug interactions (median [IQR], 3 [0-6] interactions). Incidence rate ratios of 30-day acute visits were 1.26 times greater (95% CI, 0.57-2.78) in the medium MRCI group vs the low MRCI group and 2.42 times greater (95% CI, 1.10-5.35) in the high MRCI group vs the low MRCI group. Conclusions and Relevance: Higher MRCI scores were associated with multiple dose frequencies, complicated by different dosage forms and instructions, and associated with subsequent acute visits. These findings suggest that clinical interventions to manage CMRs could target various aspects of these regimens, such as the simplification of dosing schedules.

Necrotizing Enterocolitis in Neonates With Hyperinsulinemic Hypoglycemia Treated With Diazoxide.

The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.

Safety and effectiveness of albuterol solutions with and without benzalkonium chloride when administered by continuous nebulization.

PURPOSE: The results of a study to determine if rates of poor response differ in patients receiving continuous nebulized albuterol (CNA) therapy with or without the preservative benzalkonium chloride are presented. METHODS: A retrospective analysis of the records of all patients who received CNA therapy at a large academic medical center from July 2015 to January 2016 was conducted. Data from patient evaluations performed before and after a change to benzalkonium chloride-containing albuterol were collected. The primary outcome was the rate of poor patient response, defined as a composite endpoint. Secondary outcomes included duration of therapy, dosing requirements, and duration of supplemental oxygen therapy. RESULTS: There was no significant difference in rates of poor response between patients exposed (n = 80) and patients not exposed (n = 48) to benzalkonium chloride (16% and 17%, respectively; p = 0.95). The cohort not exposed to benzalkonium chloride had a median CNA duration of 7.0 hours, as compared with 10.5 hours for the cohort exposed to benzalkonium chloride, but this difference was not significant (p = 0.19). There were no significant differences between the benzalkonium chloride-exposed and nonexposed cohorts in the maximum dosing requirement (12.6 mg/hr versus 12.8 mg/hr, p = 0.89) or median duration of supplemental oxygen use (27.5 hours versus 16.5 hours, p = 0.77). CONCLUSION: A study of hospitalized patients receiving CNA detected no significant difference in the frequency of poor response to therapy between groups receiving benzalkonium chloride-free versus benzalkonium chloride-containing albuterol products.

Impact of Early Versus Late Diuretic Exposure on Metabolic Bone Disease and Growth in Premature Neonates.

OBJECTIVES: This study aimed to determine whether there are differences in the incidence of metabolic bone disease (MBD) between preterm neonates first exposed to diuretics prior to 2 weeks of life versus those exposed after 2 weeks. METHODS: This study was a retrospective analysis of premature neonates born at a tertiary care center between 2011 and 2015 who received either furosemide or chlorothiazide. The primary outcome was incidence of MBD. Secondary outcomes included growth, electrolyte disturbances, oxygen requirement, and length of stay. RESULTS: A total of 147 patients were included. Early initiation (n = 90) and late initiation (n = 57) arms were balanced with respect to birth weight and gestational age. There was no difference in incidence of MBD in the early group (76%) versus the late group (65%; p = 0.164). Stratification by cumulative dose showed incidence of 85% in patients receiving ≥8 mg/kg of furosemide, compared with 68% and 64% of those in the <4 mg/kg and 4 to 7.9 mg/kg strata, respectively (p = 0.06). The early group experienced greater reductions in length-for-age growth during diuretic therapy (-70% versus -40%; p = 0.009). Electrolyte abnormalities were more prevalent in the early group. Although there was no difference in duration of mechanical ventilation, duration of supplemental oxygen requirement was reduced in the late group (75 versus 89 days; p = 0.003). CONCLUSIONS: Timing of diuretic initiation did not affect incidence of MBD. Increased cumulative furosemide exposure may be associated with higher incidence. Patients first exposed to diuretics within 2 weeks of life are at higher risk for electrolyte abnormalities and reduced growth velocity.