The FDA (1992) proposed to amend labeling requirements for prescription drugs to promote their safe and effective use in children. Misunderstandings and concern about legal and ethical implications have limited clinical research in pediatric populations. The newly proposed guidelines provide alternative ways to assess effectiveness and safety in children without necessarily having to conduct comprehensive studies. Results from well-controlled studies in adults can be extrapolated to children under some circumstances, although separate pharmacokinetic studies are needed to establish appropriate pediatric dosage regimens. The intent of the proposed amendment is to provide more complete information on labeling of prescription drugs concerning use and possible hazards for children.

Several instances of severe adverse effect from pharmaceutical agents in pediatric populations have attracted widespread attention. During the 1950s, chloramphenicol produced a pallid cyanosis, which progressed to circulatory collapse and death in some newborns (Sutherland, 1959). This so-called gray baby syndrome has been attributed to the diminished hepatic glucuronide conjugation and renal secretory capacities of newborns. Weiss et al. (1960) reported blood half-lives of 26, 10, and 4 hours for chloramphenicol at birth, at 10 to 16 days of age, and in children 4 to 5 years old, respectively. Thus, there is a substantial increase in chloramphenicol metabolism and excretion capacity during the first days and weeks of life. Decreased metabolic and excretory capacities of newborns and neonates have been associated with exaggerated toxicity of a number of other chemicals, including benzyl alcohol (Gershanik et al., 1982), hexachlorophene (Tyrala et al., 1977), and diazepam (Nau et al., 1984). The hexachlorophene poisonings appeared to be associated with increased percutaneous absorption as well as deficient metabolism in newborns. Floppy infant syndrome in babies born to mothers given diazepam is apparently the result of a number of age-dependent factors, including a smaller volume of distribution and thus greater target organ concentrations of the lipophilic drug due to a smaller adipose tissue volume in newborns, increased amounts of free diazepam due to displacement of the drug from plasma protein binding sites by elevated free fatty acid levels, and a prolonged half-life as a result of diminished oxidative and conjugative metabolism (Warner, 1986). As discussed in Chapter 2, most physiological processes that govern the kinetics of drugs and other chemicals mature during the first year after birth. Indeed, profound changes in some processes (e.g., phase I and II metabolism) occur during the first days and weeks of life (Morselli, 1989). Thus, the most pronounced differences from adults in susceptibility to drug toxicity would be expected in newborns, neonates, and infants; the youngest are most likely to experience the most aberrant responses.

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