An Algorithm to Identify Compounded Non-Sterile Products that Can Be Formulated on a Commercial Scale or Imported to Promote Safer Medication Use in Children.

Varsha Bhatt-Mehta,Jeffrey J Cies,Raimar Löbenberg,Ibolja Cernak,Richard H Parrish Ii,Robert B Macarthur

doi:10.3390/pharmacy3040284

Abstract

The lack of commercially-available pediatric drug products and dosage forms is well-known. A group of clinicians and scientists with a common interest in pediatric drug development and medicines-use systems developed a practical framework for identifying a list of active pharmaceutical ingredients (APIs) with the greatest market potential for development to use in pediatric patients. Reliable and reproducible evidence-based drug formulations designed for use in pediatric patients are needed vitally, otherwise safe and consistent clinical practices and outcomes assessments will continue to be difficult to ascertain. Identification of a prioritized list of candidate APIs for oral formulation using the described algorithm provides a broader integrated clinical, scientific, regulatory, and market basis to allow for more reliable dosage forms and safer, effective medicines use in children of all ages. Group members derived a list of candidate API molecules by factoring in a number of pharmacotherapeutic, scientific, manufacturing, and regulatory variables into the selection algorithm that were absent in other rubrics. These additions will assist in identifying and categorizing prime API candidates suitable for oral formulation development. Moreover, the developed algorithm aids in prioritizing useful APIs with finished oral liquid dosage forms available from other countries with direct importation opportunities to North America and beyond.

Highlights

Childhood illnesses often require the use of medications under the premise of “off-label” use.In February 2014, the American Academy of Pediatrics (AAP) released a policy statement from its Committee on Drugs regarding the off-label use of drugs in children [1]
A reliable formulation will ensure optimal clinical outcomes, and assure reproducibility in manufacturing and increased stability. This gap between commercial availability and clinical utility is bridged daily primarily by the efforts of compounding pharmacists, especially in the hospital setting, where active pharmaceutical ingredients (APIs) are extemporaneously compounded from adult solid oral dosage forms to provide medications that otherwise are not available to vulnerable pediatric populations, such as children with cardiovascular disease, cancer, cystic fibrosis, organ transplants, and other life threatening conditions
Class II molecules are best suited for formulation using hot-melt extrusion (HME) technologies Incorporating Biopharmaceutical Classification System (BCS) classification and HME application into the final selection of candidate APIs, the following class II molecules are suggested for formulation and development: metoprolol, clopidogrel, spironolactone, and nifedipine

Summary

Introduction

Childhood illnesses often require the use of medications under the premise of “off-label” use. For the purpose of the statement the Committee defined “off-label” use as that use which is not included in the package insert (US Food and Drug Administration (US-FDA)-approved labeling) for that drug and is “neither experimentation nor research” [1]. Such off-label use of drugs in children does not require any oversight by any institutional committee, Investigational Review Board, or federal regulatory agency. Off-label use combined with use of medication management systems designed for adults and adapted for use in children can compound the risk of adverse events due to increased potential for medication errors.

Why Is off-Label Use of Drugs in Children Still a Problem?

Clinical and Market Considerations

Scientific and Production Considerations—Applying BCS and HME

Conclusions