Patterns of Off-Label Prescribing in the Pediatric Intensive Care Unit and Prioritizing Future Research

OBJECTIVES: To characterize off-label prescribing among US pediatric intensive care units (PICUs), determine characteristics associated with off-label use, and identify medications in highest need for additional study. METHODS: Medications prescribed for ≥1% PICU patients (age < 18 years) in 2010 were identified from 39 children's hospitals. Use in a patient younger than the Food and Drug Administration (FDA)-approved age for any indication was considered off-label. Hierarchical multivariable modeling was used to identify characteristics associated with off-label use, accounting for center effects. Highest-impact drugs were defined by: 1) high off-label use (off-label use in at least 5% of the PICU cohort), 2) high risk medication, and 3) high priority status by the FDA or Best Pharmaceuticals for Children Act (BPCA). RESULTS: A total of 66,896 patients received ≥1 medication of interest (n = 162) during their PICU stay. A median of 3 (interquartile range, 2–6) unique drugs per patient were used off-label. Those who received ≥1 drug off-label (85% of the cohort) had longer median PICU (2 days vs 1 day) and hospital (6 days vs 3 days) lengths of stay and higher mortality (3.6% vs 0.7%), p < 0.001. Factors independently associated with off-label drug use included: age 1 to 5 years, chronic conditions, acute organ failures, mechanical ventilation, arterial or venous catheters, dialysis, and blood products. Half of prescribed medications (n = 84) had been used off-label: 26 with significant off-label use, 30 high-risk medications, and 47 with high FDA/BPCA priority. The highest impact medications identified were: dexmedetomidine, dopamine, hydromorphone, ketamine, lorazepam, methadone, milrinone, and oxycodone. CONCLUSIONS: Most PICU patients are exposed to off-label medication use, with uncertain evidence. Future medication research in this population should focus on medications with high impact potential.

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Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit

Medicina Intensiva (English Edition) ◽

10.1016/j.medine.2014.11.007 ◽

2016 ◽

Vol 40 (1) ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

E. Blanco-Reina ◽

A.F. Medina-Claros ◽

M.A. Vega-Jiménez ◽

R. Ocaña-Riola ◽

E.I. Márquez-Romero ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Pediatric Intensive Care Unit ◽

Drug Utilization ◽

Pediatric Intensive Care ◽

Off Label Use ◽

Utilization Pattern ◽

Off Label ◽

Label Use

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Safety of Clofarabine with Multiagent Chemotherapy in Childhood High Risk Relapse of Acute Lymphoblastic Leukemia (Vandevol study of the French SFCE Acute Leukemia Committee).

Blood ◽

10.1182/blood.v120.21.2570.2570 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2570-2570

Author(s):

Brigitte Nelken ◽

Guy Leverger ◽

Claire Galambrun ◽

Genevieve Plat ◽

Claudine Schmitt ◽

...

Keyword(s):

High Risk ◽

Dose Level ◽

Bacterial Infections ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Off Label Use ◽

Childhood All ◽

Off Label ◽

Post Transplant ◽

Label Use

Abstract Abstract 2570 Background. Current outcome of very early relapse of ALL in children remains poor. Clofarabine, a novel nucleoside analog has proven effective as a single agent in childhood ALL second relapse, providing a CR+CRp ratio of 20 to 28 % (Jeha 2006, Kearns 2006). Clofarabine in combination with cyclophosphamide and Etoposide provided a 44% overal response rate rate in children with advanced ALL (Hijiya 2011) and further multi-drug combinations need to be investigated. The VANDA regimen that has proven effective in high risk ALL and in ALL relapse (Domenech 2008) was used as a template, Cytarabine being replaced by Clofarabine in this combination. Procedure. A phase I study combining escalating doses of Clofarabine with fixed doses of Mitoxantrone, Etoposide, Asparaginase and Dexamethasone was undertaken in children presenting very early (18 months or less after initial diagnosis) medullary or combined ALL relapse or children with second relapse or post transplant relapse. A 3+3 rolling design was used for escalating clofarabine doses with 25% increments from 20 to 40mg/m2/d. Results. Sixteen patients were enrolled, eleven in first marrow relapse, four in second relapse. One patient with an initially refractory disease was secondary excluded as he didn't fulfill the inclusion criteria. Four patients had previously been allografted. Three patients were enrolled at dose level 1 (clofarabine 20 mg/m2), and 3 patients at dose level 2 (clofarabine 26 mg/m2) without any significant dose-limiting toxicity (DLT). Six patients were enrolled at dose level 3 (clofarabine 32 mg/m2), one patient experienced a liver DLT (gamma GT elevation) exceeding 7 days. At the last planned dose level (clofarabine 40 mg/m2), two patients had a grade 3 transaminase elevation exceeding 7 days and 2 patients had a severe fungal infection. Median duration of neutropenia was 20 days (15–31). Other expected toxicities included 3 documented bacterial infections, 3 mucosal toxicities needing parenteral support, one lung aspergillosis, one transient insulin dependant hyperglycemia. There was no toxic death. Out of 15 evaluable patients, 11 (73%) achieved a complete cytological remission (CR). 4 relapses occurred at 1, 1, 2 and 3 months. 6 patients proceeded to allo-SCT with 2 second allografts. One allografted patient died from EBV-PTLD, the others are alive at 2, 13, 13, 15, and 29 months post-transplant. Conclusion. Clofarabine in combination with four major antileukemic drugs appeared feasible and effective in inducing complete remission in those high risk patients. Clofarabine MTD was 32 mg/m2/d for five days and this dose step is currently being expanded to a total of 10 patients, before a phase II study will be proposed for early and very early ALL relapses. Study registered at ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT01279096). Disclosures: Off Label Use: off label use of clofarabine.

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Medication Use in the Neonatal Intensive Care Unit: Current Patterns and Off-Label Use of Parenteral Medications

The Journal of Pediatrics ◽

10.1016/j.jpeds.2007.07.050 ◽

2008 ◽

Vol 152 (3) ◽

pp. 412-415.e1 ◽

Cited By ~ 56

Author(s):

Praveen Kumar ◽

Jennifer K. Walker ◽

Kristin M. Hurt ◽

Kimberly M. Bennett ◽

Neal Grosshans ◽

...

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Neonatal Intensive Care ◽

Medication Use ◽

Off Label Use ◽

Off Label ◽

Label Use

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Off-label use of drugs in neonatal intensive care units

Indian Pediatrics ◽

10.1007/s13312-014-0468-y ◽

2014 ◽

Vol 51 (8) ◽

pp. 644-646 ◽

Cited By ~ 17

Author(s):

Suksham Jain ◽

Shiv Sajan Saini ◽

Deepak Chawla ◽

Praveen Kumar ◽

Shashikant Dhir

Keyword(s):

Intensive Care ◽

Intensive Care Units ◽

Neonatal Intensive Care ◽

Neonatal Intensive Care Units ◽

Off Label Use ◽

Off Label ◽

Label Use

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Pharmacovigilance Data as a Trigger to Identify Antimicrobial Resistance and Inappropriate Use of Antibiotics: A Study Using Reports from The Netherlands Pharmacovigilance Centre

Antibiotics ◽

10.3390/antibiotics10121512 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1512

Author(s):

Jean Marie Vianney Habarugira ◽

Linda Härmark ◽

Albert Figueras

Keyword(s):

Antimicrobial Resistance ◽

The Netherlands ◽

Pathogen Resistance ◽

Future Research ◽

Pharmacovigilance Centre ◽

Off Label Use ◽

Off Label ◽

Inappropriate Use ◽

Product Use ◽

Label Use

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and pharmacovigilance has the potential to strengthen current antimicrobial stewardship strategies. This study aimed to characterize AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre; (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs); (3) Results: Between 1998 and January 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n = 89; 35%), colistin (n = 30; 11.9%), cipro-floxacin (n = 16; 6.3%), doxycycline (n = 14; 5.5%), and aztreonam (n = 12; 4.8%). The PTs used included off label use (n = 91; 36.1%), drug ineffective (n = 71; 28.2%), product use in unapproved indication (n = 28; 11.1%), pathogen resistance (n = 14; 5.6%), and drug resistance (n = 13; 5.2%). 54% of the reports were on Watch antibiotics and 19% were involved in the Reserve group. In the Watch group, “off label use” and “product use in unapproved indication” were the most frequent PTs and the majority of reports on Reserve antibiotics were coded as “Off label”. A sharp increase in the number of reports was observed in the three consecutive years with 21 in 2013, 54 in 2014, and 83 in 2015; (4) Conclusions: In addition to existing AMR monitoring strategies, pharmacovigilance databases can serve as a source of data on suspected resistance and inappropriate use. Future research should explore how these AMR-relevant MedDRA Terms are used in resource-limited settings with less capacity to generate laboratory-confirmed resistance data.

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Improved Outcome with ATRA-Arsenic Trioxide Compared to ATRA-Chemotherapy in Non-High Risk Acute Promyelocytic Leukemia – Updated Results of the Italian-German APL0406 Trial on the Extended Final Series

Blood ◽

10.1182/blood.v124.21.12.12 ◽

2014 ◽

Vol 124 (21) ◽

pp. 12-12 ◽

Cited By ~ 3

Author(s):

Uwe Platzbecker ◽

Giuseppe Avvisati ◽

Gerhard Ehninger ◽

Laura Cicconi ◽

Christian Thiede ◽

...

Keyword(s):

High Risk ◽

Arsenic Trioxide ◽

Research Funding ◽

Primary Study ◽

Intermediate Risk ◽

Off Label Use ◽

Front Line ◽

Off Label ◽

Label Use ◽

Line Management

Abstract Background: We recently showed that the combination of ATRA and arsenic trioxide (ATO) is at least not inferior and possibly superior to standard ATRA and chemotherapy (CHT) in the front-line management of low/intermediate risk APL (Italian-German APL 0406 trial; Lo-Coco et al., NEJM 2013). We report herein on the extended and final series of 276 patients (162 were in the previous report) with the last case being enrolled into the study in January 2013. Methods: The APL0406 study was a prospective, open-label, randomized intergroup trial conducted by the Italian GIMEMA and the German SAL and AMLSG study groups. Eligible patients were adults aged 18-<71 years with newly diagnosed, genetically confirmed, non-high-risk (WBC≤10x109/L) APL. Patients were randomized to receive the ATO+ATRA combination originally developed by the MD Anderson Cancer Center group, or the Italian AIDA2000 protocol (Estey et al., Blood 2006 and Lo-Coco et al., Blood 2010). Patients in the ATRA-ATO arm received ATO 0.15/kg plus ATRA 45 mg/m2 daily until CR, then ATO 5 days/week, 4 weeks on 4 weeks off, for a total of 4 courses and ATRA 2 weeks on and 2 weeks off for a total of 7 courses. Patients in the ATRA-CHT arm received the standard AIDA (ATRA+Idarubicin) induction followed by 3 cycles of anthracycline-based consolidation together with ATRA and low dose CHT and ATRA for maintenance. The primary study objective was EFS at 2 years. Results: A total of 254 patients were evaluable for response to induction. CR was achieved in 122/122 (100%) in the ATRA-ATO versus 128/132 (97%) in the ATRA-CHT arm (P=0.12). Four patients died during induction in the ATRA-CHT arm. After a median follow-up of 36 months (range 1-75 months), the 2-year EFS was 98% and 84.9% in the ATRA-ATO and ATRA-CHT groups respectively (P= 0.0002), The 2-year cumulative incidence of relapse (CIR) rate was 1.1% and 9.4%, respectively (P=0.005) and, finally, the 2-year overall survival (OS) rate was 99.1% vs. 94.4% (P=0.01) for ATRA-ATO vs ATRA-CHT, respectively. Conclusions: The data on this extended cohort demonstrate a significantly augmented survival benefit coupled to a higher antileukemic efficacy provided by ATRA-ATO as compared to ATRA-CHT, in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting. Figure 1 Figure 1. Disclosures Platzbecker: Teva: Honoraria. Off Label Use: Presentation includes off-label use of arsenic trioxide (ATO) in front-line management of APL. ATO is currently approved in treatment of relapsed APL in the US and Europe. Breccia:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Fiedler:TEVA: Travel reimbursement for meeting attendance Other. Lübbert:Cephalon / TEVA: Travel support Other. Link:TEVA: Consultancy, Speakers Bureau. Radsak:Celgene: Research Funding. Döhner:TEVA: Research Funding. Schlenk:TEVA: Research Funding, Speakers Bureau. Lo-Coco:TEVA: Honoraria; Lundbeck: Honoraria.

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Survival outcomes and practice trends for off-label use of adjuvant targeted therapy in high-risk locoregional renal cell carcinoma

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2020.02.028 ◽

2020 ◽

Vol 38 (6) ◽

pp. 604.e1-604.e7 ◽

Cited By ~ 1

Author(s):

Nicholas H. Chakiryan ◽

Ann Martinez Acevedo ◽

Mark A. Garzotto ◽

Yiyi Chen ◽

Jen-Jane Liu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

High Risk ◽

Cell Carcinoma ◽

Renal Cell ◽

Survival Outcomes ◽

Off Label Use ◽

Off Label ◽

Label Use

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Drug Utilisation and Off-Label Use on a German Neonatal Intensive Care Unit: A Retrospective Cohort Study and 10-Year Comparison

Pharmacy ◽

10.3390/pharmacy8030173 ◽

2020 ◽

Vol 8 (3) ◽

pp. 173

Author(s):

Carmen Geißler ◽

Christopher Schulze ◽

Sebastian Botzenhardt ◽

Wolfgang Rascher ◽

Antje Neubert

Keyword(s):

Intensive Care Unit ◽

Cohort Study ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Neonatal Intensive Care ◽

Drug Utilisation ◽

Off Label Use ◽

Off Label ◽

The University ◽

Label Use

Pharmacotherapy of neonates is complex and marked to a large extent of off-label use. The implementation of the Paediatric Regulation (2007) gave hope for a change in the safety and efficacy for drugs used in neonatal intensive care units (NICU). This study investigates drug utilisation patterns and off-label use in a German neonatal intensive care unit (NICU) in 2014. A 12-months retrospective, observational cohort study was performed at the NICU of the University Children’s Hospital Erlangen, Germany. Licensing status was determined using the Summary of Product Characteristics (SmPC). Results are compared with a similar study conducted 10 years earlier. The study included 204 patients (57.8% male) (2004: 183) and 2274 drug prescriptions were recorded (2004: 1978). The drugs that were mostly prescribed were drugs for the nervous system (2004: 22.6%; 2014: 26.9%) and anti-infectives for systemic use (2004: 26.0%; 2014: 24.9%);34.3% (2004) and 39.2% (2014) of all prescriptions were off-label;62.7% of all patients received at least one off-label or unlicensed drug (2004: 70%). For 13 drugs, the licensing status changed either from off-label to label (n = 9) or vice versa (n = 4). Overall, there was no significant change neither in terms of the drugs used nor regarding their licensing status. Further studies are needed to validate these findings in a European context.

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