Is Pediatric Labeling Really Necessary? Michael L. Christensen, PharmD; Richard A. Helms, PharmD; and Russell W. Chesney, MD ABBREVIATIONS. FDA, US Food and Drug Administration; For solid dosage forms, parents often must divide FDCA, Food, Drug and Cosmetic Act; GFR, glomerular filtration adult tablets in halves or quarters to get an appro- rate; BSA, body surface area. priate dose for their child. This results in imprecise dosing that can lead to poor therapeutic response. abeling refers to the label on the drug container Practitioners are left to use empiric therapy in and all printed materials, including the pack- treating their pediatric patients because of the inad- age insert, that accompanies the product. La- equate information available for prescribing of L drugs. They often must choose between not treating beling of a drug indicates that there is substantial evidence from adequate and well controlled clinical children with potentially beneficial medications be- trials for the safe and effective use of that drug. cause they are not approved for use in children, or to Labeling provides important information on clinical treat them with these medications based on adult pharmacology, indications and usage, contraindica- studies and limited or anecdotal experience in chil- tions, precautions, adverse effects, dosage, and ad- dren. In either case, children may not be prescribed ministration. Unfortunately for children, most drug optimal therapy. labeling contains the precautionary disclaimer, be- cause safety and efficacy in children have not been FOOD, DRUG AND COSMETIC ACT established. Concern for the risk to public health and safety The availability of safe and effective drugs has with unsanitary food and adulterated drugs, a com- been directly responsible for the improvement in mon problem during that time, lead to passage of health over the past 50 years. Children essentially Federal Food and Drug Act in 1906 (Table 1), which have been excluded from the benefit of the many prohibited interstate commerce in misbranded or therapeutic advances that have marked pharmaceu- adulterated food, drink, and drugs. A major stimulus tic drug development. The failure to include children for passing the act was quinine being used by the in clinical trials during drug development leads to American Army in Mexico that was found adulter- delay in implementing potentially effective treat- ated. The Act was completely rewritten as the Food, ment. Most US food and Drug Administration- Drug and Cosmetic Act (FDCA) in 1938, after the approved drugs lack approval for use in all children death of 107 children from sulfanilamide elixir that or are restricted to certain pediatric age groups, pri- used diethylene glycol as a solvent.2 No toxicity test- marily older children.1 Only a few of the new drugs ing had been done on the product before marketing. released in this country each year are approved for Also, new drugs had to be labeled with adequate use in children. This lack of information on the safe directions for use. A problem with the latter require- and effective use of drugs in the most vulnerable ment was that many newer drugs being developed patients, infants and neonates, is of greatest concern. and coming onto the market were not safe for use Only five of the 80 most frequently used drugs have except under medical supervision. These drugs did been approved for use in this population. Another not meet the adequate directions for use require- problem is that most drugs are not available in suit- ment. A 1951 amendment to the FDCA solved the able pediatric dosage forms. They are not available in problem by establishing two classes of drugs: over- appropriate dosage sizes, lack liquid formulation, the-counter drugs that could maintain adequate di- and taste peculiar to the child, making compliance rections for use on the label, and prescription drugs difficult. Pharmacies extemporaneously prepare that could only be used under medical supervision. many drugs in liquid dosage forms for use in chil- Another pediatric tragedy, this time fetal malfor- dren. These dosage forms are not sufficiently tested mation from maternal ingestion of thalidomide, led to determine stability, efficacy, or expiration dating. to an amendment in 1962 that drugs not only had to be safe, but also effective in the population for which they were to be marketed.3,4 The safety and efficacy From the Departments of Pediatrics and Clinical Pharmacy, Pediatric Phar- in one population could not be transferred to an- macology Research Unit, Center for Pediatric Pharmacokinetics and Ther- apeutics, The University of Tennessee, and Crippled Children’s Foundation other. Thus, safety and efficacy in adults cannot be Research Center, LeBonheur Children’s Medical Center, Memphis, Ten- applied to children. These two significant changes to nessee. the FDCA were the result of therapeutic tragedies in Received for publication Mar 30, 1999; accepted Mar 31, 1999. children. Remarkably, the problem recognized with Address correspondence to Russell W. Chesney, MD, Department of Pedi- atrics, 50 N Dunlap, Memphis, TN 38105. the use of medications in children and the amend- PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad- ments to the FDCA has not encouraged increased emy of Pediatrics. study of drugs in children. On the contrary, it has Downloaded from www.aappublications.org/news byPEDIATRICS guest on September Vol. 24, 104 2021 No. 3 September 1999 593 TABLE 1. Major Food and Drug Acts Excessive mortality and an increased incidence of 1906 Prohibited adulterated or misbranded products kernicterus among premature neonates receiving a 1938 Drugs must be proven safe and have adequate directions sulfonamide antibiotic also were described in the for use 1950s.8 1962 Drugs also must be effective in the intended population Reports of therapeutic disasters continued in the 1979 Pediatric labeling emphasized 1994 Final Rule clarifies pediatric labeling procedures 1980s. A clinical syndrome consisting of ascites, liver and renal failure, thrombocytopenia, and death among low birth weight infants exposed to E-Ferol discouraged the evaluation of drugs in children be- was reported.9,10 The product had not been tested for cause of perceived concerns over ethical issues, fears safety before marketing. The reputed causative of harming children, and perceived increased liabil- agents were the mixture and quantity of polysorbate ity in testing drugs in children. Children also repre- 80 and polysorbate 20, which were used as solvents sent a small market share for most drugs, which in the product. Premature infants given 10 mL of discourages sponsors from pursuing drug labeling MVI-12, the usual adult dose of a product intended for children. to be used in adults, developed marked serum hy- The recognition that only a minority of drugs were perosmolality caused by the propylene glycol.11,12 labeled safe and effective for use in children led to The toxicity of oral ingestion of propylene glycol is the 1979 US Food and Drug Administration (FDA) well known. Toxic effects include seizures, hepatic regulations that specific pediatric indications, if any, damage, renal impairment, and hyperosmolality. are described in the indications and usage section of Propylene glycol and polysorbate are common sol- the labeling, with appropriate pediatric dosage pro- vents used in drug preparations including cotrimox- vided in the dosage and administration section.5 The azole, digoxin, phenytoin, phenobarbital, diazepam, Act also requires that recommendations for pediatric MVI-12, etoposide, and teniposide. Finally, neonates use be based on substantial evidence derived from exposed to large amounts of benzyl alcohol experi- adequate and well controlled studies in the pediatric enced kernicterus, intraventricular hemorrhage, met- population, unless the requirement was waived. The abolic acidosis, and death, or “gasping syn- pediatric use subsection was intended to encourage drome.”3,14 Benzyl alcohol, a bacteriostatic agent, is drug labeling in pediatric patients. As with the 1962 found in many intravenous products, including the amendment, it had the opposite effect. The require- bacteriostatics saline often used to flush intravenous ment further discouraged pediatric labeling for most catheters. Immaturity of detoxification of its benzoic drugs because it required extensive data in the in- acid metabolite in premature neonates appears re- tended population. Surveys continued to show that sponsible for the toxicity. the vast majority of newly approved drugs do not carry pediatric labeling. The FDA, concerned that EXTRAPOLATING DATA FROM ADULTS TO without adequate information practitioners may be CHILDREN reluctant to prescribe certain drugs for their pediatric Extrapolating dosing information from adults im- patients or may prescribe them inappropriately, plies that children are simply small adults. We pressed for implementation of the 1994 Final Rule for clearly recognize that the effects of many drugs on pediatric labeling.5 The Rule clarifies the FDA posi- infants and children may vary considerably from the tion on various procedures that can be used to get effects seen in adults. The most distinguishing fea- pediatric labeling of drugs. The Final Rule also ture differentiating children from adults are the sig- placed greater responsibility on the sponsor to justify nificant physical and maturation changes that occur. why pediatric labeling should not occur for the drug. Ontogeny of drug absorption, metabolism, and ex- In certain cases, drugs may be labeled for pediatric cretion restricts substantially the ability to extrapo- use based on adequate and well controlled studies in late data from adults to children. adults, with pharmacokinetic and safety data in chil- The gastric pH at birth is neutral and falls during dren. The Final Rule also recognizes the hazards that the first 48 hours.15 There appears to be a biphasic inactive ingredients can pose to the pediatric popu- pattern to gastric and secretion in neonates. High lation. Compliance with the Final Rule by the phar- acid concentrations are seen in the first 10 days, maceutics industry is not clear at this time.