adverse drug events in children: the us food and drug administration perspective

VoL. 62, No. 10, OCTOBER 2001

Adverse Drug Events in Children: The US Food and Drug Administration Perspective William Rodriguez, MD, Rosemary Roberts, MD, and Dianne Murphy, M D

Office of Review Management and Office of Drug Evaluation IV, Center for Drug Evaluation and Research, US Food and Drug Administration, Department of Health and Human Services, Rockville, Maryland

ABSTRACT Background: Adverse events are unwelcome occurrences associated with

drug use. Some of these events are predictable or preventable, whereas others are idiosyncratic. The "off-label" use of drugs in pediatric patients further com- plicates the assessment of adverse events because pediatric dosing based on recommended adult doses may not be appropriate. Adverse events often occur in pediatric patients in an environment of incomplete information about the drug's pharmacokinetics in the pediatric population, and the inherent metabolic differences between adults and children may not be detected with ex- trapolating maneuvers. Adverse event information may be acquired during the drug development process, including the preclinical, preapproval, and postapproval processes. However, the lack of clinical trials in pediatric patients indi- cates that such information is not available.

Objective: This paper reviews the pharmacologic basis for the different types of adverse events in children and adults and provides examples of the differences between these 2 groups.

Methods: Data from spontaneous reports of adverse events that support a trend may assist with initiating and identifying an early signal for an adverse event and an assessment of its occurrence. We summarized our experience with the exclusivity initiative aimed at improving the acquisition of knowledge about use of drugs in children. We also summarized the data available from some spontaneous adverse event reports as well as examined pertinent litera- ture to provide state-of-knowledge information on the specific adverse events.

Results: Of the first 16 products that were subsequently studied in children, 6 (37.5%) had significant changes in labeling that had an impact on safety or efficacy. Specifically, we were able to identify situations in which proposed dosing could have led to overdosing or underdosing. We also identified situations in which adverse events, previously undescribed, could be expected.

Presented at the Workshop on Adverse Events in Pediatrics, Rockville, Maryland, April 9-10, 2001.

Accepted for publication July 19, 2001. Printed in the USA. Reproduction in whole or part is not permitted. 0011-393X/01/$19.00

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CURRENT THERAPEUTIC RESEARCH ®

Conclusions: This information provides a better understanding of potential reasons for adverse events and defines unique pediatric adverse events. The exclusivity initiative supports the need for formal studies in the pediatric population if the therapy is to be used in children.

Key words: adverse events, off-label use, pediatric drugs, exclusivity initiative. (Curt Ther Res Clin Exp. 2001;62:711-723)

INTRODUCTION "Primum non nocere" has been a guiding force in the practice of medicine. The US Food and Drug Administration (FDA) operates under the commitment to approve safe and effective drugs. However, until recently, for various reasons, children have been "therapeutic orphans," a phrase coined in 1963 by Shirkey. 1 This phrase refers to the fact that children may have been denied the use of many new drugs because only a small portion of these drugs were studied in the younger population. Since 1962, many drugs have carried an "orphaning" clause, cautioning about their use in all children or in a specific age group. 1 In practice, many physicians have still used these drugs in the "orphaned" population despite the lack of efficacy, safety, and dosing data from controlled trials. This "off-label" use of drugs in pediatric patients is supported by assumptions based on extrapolation from the adult experience. Such an approach assumes that the condition or disease in the child is similar to that in the adult, and often does not correct for pharmacologic or metabolic changes that occur through infancy and childhood. The lack of information makes it more difficult to as- certain or predict the nature of adverse events that may occur in the pediatric population.

A review of the development of the FDA identifies pivotal events associated with pediatric drug use that subsequently led to legislation aimed at protecting the public. 2 For example, in 1901, a 5-year-old child developed tetanus 2 days after receiving diphtheria antitoxin. Thirteen other children had similar problems traced to an antitoxin supply prepared by the St. Louis Board of Health from a tetanus-infected horse. This occurrence played a major role in the 1902 congressional enactment of the Biological Control Act, which ensured purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans.

In 1937, sulfanilamide, a new "wonder drug" antimicrobial, was developed as a pediatric formulation. To dissolve the rather insoluble sulfanilamide and make it taste good, the pharmacist concocted a raspberry syrup of acceptable taste and odor with the vehicle diethylene glycol; 107 patients, many of them children, died of renal failure.

In 1938, the Food, Drug, and Cosmetic Act was passed, requiring proof of safety before marketing was allowed. Many years elapsed before the thalidomide disaster, when this drug was linked with fetal malformations in Europe.

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The experience with thalidomide (which was not approved in the United States) led to the 1962 Amendment to the FDA regulations. Not only did manufacturers have to prove that a drug was safe, but also that it was effective. Furthermore, the concept of informed consent was emphasized and included in the regulations. Starting in June 1979, drug labels had to address the pediatric population. Subsequently, however, most applications would simply state that safety and effectiveness below a certain age had not been established.

The issue of prescribing drugs for the pediatric population concerns the FDA for several reasons: First, it is part of the FDA mandate to ensure the effectiveness and safety of drugs for all citizens, including children. Second, children are in an active process of physical growth and development, and they have immature detoxifying mechanisms. Third, children are in double jeopardy for potential over- and underdosing. If studies have not been done to establish the appropriate dose for therapeutic levels, the recipient child is placed in a posi- tion of assuming all the potential risk(s) without any of the benefits. Finally, use of a drug without appropriate knowledge of pharmacokinetics (PK) and pharmacodynamics or side effects in the pediatric population may result in unde- sirable effects, which may be short term, long term, or both. Short-term effects could include undertreatment, resulting in failure of therapy or lack of control, or overtreatment with its potential for inherent side effects, including the pos- sibility of toxicity. Long-term effects, such as unforeseen or unplanned arrests of growth and development, could follow. 3 In addition, medication dose errors in pediatric patients are an important cause of adverse events. 4 If we haven't approached the administration of a specific drug in an evidence-based fashion, how are we to avoid improper use?

This paper reviews the pharmacologic basis for the different types of adverse events in children and adults and provides examples of the differences between these 2 groups.

PHARMACOKINETICS AND PHARMACODYNAMICS IN DEVELOPING ORGANISMS Children are rapidly developing organisms, and postnatal growth and development may be affected by drug exposure. Although cell division continues after birth, most growth is accretionary from the accumulation of extracellular ma- trix and accumulation within differentiated cells of fat, protein in muscle, and hormones.

After birth, the central nervous system (CNS), pulmonary, renal, muscular, skeletal, reproductive, and immune systems continue to develop. For example, despite attaining most of its cellular division by 6 months of age, the CNS continues to grow through adolescence by migration, differentiation, and myelinization. Some developmental landmarks that may have an impact on adverse events or drug effectiveness in pediatric patients are shown in Table I. s-7

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Table I. Some developmental landmarks that may have an impact on a drug's activity and effectiveness. 5-z

System Critical Age

Central nervous system Receptor development

Monoamine system Glutamate

End of rapid myelinization Pulmonary

Onset of alveoli formation Completion of alveoli formation

Renal Glomerulogenesis and nephrogenesis Adult glomerular filtration rate and

tubular secretion

Maximum densities 2 to 4 years Peak binding in cortex 1 to 2 years;

decline to adult levels 2 to 16 years 2 years

Gestation day 252 2 years

Gestation week 36

Few weeks to 6 months

ADVERSE EVENT ASSESSMENT Assessment of adverse events is a complex process that must take into con- sideration the effects of short-term or continuous exposure on acute and long- term outcomes. These events may be expected or idiosyncratic. 8'9 Studies that look at the short-term effect of cort icosteroid exposure may only report the acute effect and fail to assess the long-term consequences, such as the medication's effect on the hypothalamic-pituitary-adrenal (HPA) axis and the sub- sequent influence on growth or other neuroendocrine targets. 3

One area of major concern and debate has been the effect of drugs on the CNS. For example, psychotropic agents and anticonvulsants may have an un- recognized effect on cognition or behavioral development in children, whereas use of some anticonvulsants (eg, phenobarbital) may result in sedation or paradoxically be associated with akathisia in pediatric patients. 1°

Anticonvulsants may have long-term effects on school performance and attention span. 1° Similarly, neuroleptics can inhibit release of growth hormone and lead to breast enlargement in male patients~t; other drugs may have a proconvulsant effect. ~2

DIFFERING ADVERSE EVENTS IN ADULTS AND CHILDREN Although some age-dependent effects can largely be predicted with knowledge of a drug's metabolic pathways, others cannot. Hence, it may be difficult to extrapolate adult safety information to children. The inherent difference between mature and immature body systems introduces the possibilities of drug toxicity or resistance to drug toxicity in immature systems that are not observed in mature systems.

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Table II. Examples of toxicity in pediatric versus adult patients.

Increased toxicity 13-16 Chloramphenicol in newborns Tetracyclines in infants and children Benzyl alcohol in intravenous fluid in premature babies and neonates

Decreased toxicity 1 z-19 Aminoglycosides in newborns Acetaminophen acute overdose in young children

Table II shows examples of drugs associated with increased 13-16 or decreased ~7-~9 toxicity in pediatric populations compared with adults. In the case of chloramphenicol, the drug's half-life is longer in children than in adults due to immature metabolic processes, which explains the increased toxicity that occurs when this agent is used in newborns) 3 In the case of acetaminophen, young children have higher rates of glutathione turnover as well as more rapid sulfation, resulting in a greater capacity to detoxify an overdose compared with adults) 7

PRECLINICAL INFORMATION TO ADDRESS THE PROBLEM What tools do we have to ensure drug safety in pediatric patients? No standards yet exist for studies in juvenile animals. Animal studies might reinforce or reassure us in areas where safety cannot reasonably or safely be assessed in humans, but may not capture the effect on the developmental processes specific to the age group. However, even though species differences are known, juvenile animal studies could be used when (1) long-term use of a drug is contemplated, (2) information on specific toxicity (eg, neurotoxicity) is needed, or (3) drug class problems (eg, bone and joint effects in animals or adult humans) are known. 2° For example, the neonatal toxic effects of hexachlorophene would have been predicted by work in experimental animals. 2~

Several considerations may guide the use of juvenile animal studies: (1) if hazards are identified in animals, these findings should be followed up; (2) if off-label use signals adverse events but a specific relationship is not known; or (3) if clinical adult data are lacking. Such an approach is supported by experience: The effect of phenobarbital on cognitive performance was predicted by experimental studies in the developing rodent system. 1°

REGULATORY DEVELOPMENT Preapproval Although the FDA has one of the most rigorous preapproval processes in the world, clinical trials cannot uncover every safety problem or be expected to do so. The length of the clinical trial or the number of people receiving the products might not be sufficient to demonstrate adverse events. Overall, shortcom- ings of the current system include (1) studies of short duration, which may miss effects observed with chronic use or long latency; (2) narrow, highly selected

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populations, in which exposure in children and the elderly may be missed; (3) a narrow set of indications that fails to look at evolving use; and (4) a limited number of patients exposed in preapproval trials (generally 3000 to 4000), which makes rare events difficult to detect. In pediatric drug development, if PK studies are requested instead of formal efficacy studies, long-term observation is usually not part of this initial process. In certain situations, one might con- sider long-term studies for certain drugs (eg, steroids or neuroleptics), which could affect growth and development; drugs that affect neurotransmitters and are administered chronically during CNS/brain development; and drugs with known CNS toxicity. Drugs with suspected effects on the musculoskeletal system (eg, quinolones) also should be assessed with long-term studies. 2° Table III lists examples of drugs or classes of drugs that have been associated with pediatric adverse events. 11'21-28

Postapproval Awareness of adverse drug events could come from studies or be captured by a spontaneously generated system. The advantage of the latter is its ability to capture rare events after large numbers of individuals have received a therapy. Increased reporting can trigger further assessment, initiate assessment, or point toward trends. Although postapproval reporting of adverse events is in place, it is not a flawless system. Weaknesses include underreporting, the pos- sibility of duplication, and frequent lack of details. Two other systems (ie, data mining and MedWatch) may also be used.

Table III. Drugs associated with pediatric adverse events. 11'21-28

Drug Adverse Event

Verapamil

Spironolactone Chronic steroid use in collagen

vascular disease Doxorubicin Retinoids Aspirin Dermatologic products

(containing adrenocorticosteroids) Psychotropic products

(under analysis) Topical agents

(hexachlorophene) Tricyclics

Cardiovascular events in children younger than 1 year

Hypotension Complete atrioventricular block

Gynecomastia

Growth retardation Cardiotoxicity Pseudotumor cerebri Reye's syndrome Hypothalamic-pituitary-adrenal axis suppression

susceptibility

? Effect on height and weight gain

Neonatal neurotoxicity Electrocardiographic abnormalities in young

children

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Data Mining The data mining system uses DuMouchel's statistical algorithms 29-3s coupled with visualization tools 36'37 to systematically search the FDA's database of spontaneous reports for safety signals that are higher than expected. The system analyzes combinations of event codes and drug names, and covariates such as patient age and sex. Signal scores associated with adjusted observed/ expected (O/E) ratios quantify the deviations from what would be expected under the assumption of no association between drug and event. These higher- than-expected signals require further follow-up interpretation. The estimated lower limit of the 95% confidence interval of the adjusted O/E (EB05) is used as a signal score. Signal scores >2 are considered positive signals that require further follow-up and interpretation. 3s

Table IV depicts positive signals generated for some pediatric products. Such a report points to areas of potential problems that may warrant further investigation to address questions such as: Could (or does) the disease being treated have these events associated with it, and what is the expected rate of occurrence?

The terms suspect and serious are used as follows: Suspect cases are drugs considered to be associated with an adverse event by prescribers submitting reports to the FDA or to drug manufacturers. For a given report, however, it is unknown whether the suspect drug caused the event. Events may be related to an underlying disease or condition or to the use of concomitant drugs, or they may have occurred by chance. Serious adverse events are adverse experiences that result in any of the following outcomes: death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a

Table IV. Positive signals* in spontaneous reports of adverse drug events (suspect and serious only) in pediatric patients, t

Drug Signal No. of Cases

Pancrelipase Ceftriaxone

Isoflurane Isotretinoin Fluticasone propionate Nitric oxide

Intestinal obstruction NOS Cholelithiasis Renal calculi NOS Hyperpyrexia malignant Hyperlipidemia NOS Adrenal insufficiency NOS Cardiac arrest Death Respiratory failure (excluding neonatal) Neonatal respiratory failure

41 32 18 28 12 10

9 8 7 3

NOS = not otherwise specified. *Higher than expected. *From the Data Mining system, provided by Ana Szarfman, MD, PhD, Medical Officer, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, Maryland.

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persistent or significant disability or incapacity, or a congenital anomaly or birth defect.

MedWatch MedWatch, 39'4° the FDA Safety Information and Adverse Event Reporting Pro- gram, is a system in which formal spontaneous reports of adverse events are analyzed through the effects of postmarketing drug risk assessments. Each serious adverse event is reviewed individually, analyzed and contrasted to the user population, and corrected to drug utilization data, market surveys, and third-party payers (caveat: pharmacoepidemiologic studies do not necessarily equal drug usage). Table V shows one such report involving valproate sodium/ divalproex sodium/valproic acid and its use in patients 0 to 18 years of age. Sixty patients developed pancreatitis, and information such as use of other medications and onset of symptoms from beginning of exposure was provided for those patients. Seven deaths were reported. Extant reports of hepatic fatalities also are associated with the use of this product. 41

Exclusivity Initiative The pediatric exclusivity initiative 42 rewards innovators with 6 months of additional marketing exclusivity for conducting pediatric studies in response to a written request issued by the FDA. Between July 1998 and March 1, 2001, 27 products were granted such exclusivity following submission of the requested pediatric studies and fulfillment of the terms of the written request. Sixteen products have been labeled, 6 (37.5%) of which have significant changes in safety or dosing. Table VI shows the specific information that was discovered in pediatric studies and compares it with the information available in the Phy- sicians' Desk Reference. 43 Specifically, the lower end of the dosing range was required to avoid respiratory distress in children with congenital heart disease and pulmonary hypertension who receive midazolam, and patients on gabapentin who were younger than 5 years required higher doses for efficacy. Pe- diatric patients receiving etodolac needed mg/kg doses 2 to 3 times higher than those required for efficacy in adults, whereas patients 2 to 5 years of age and

Table V. US Food and Drug Administration case reports of pancreatitis possibly related to valproate sodium/divalproex sodium/valproic acid in children 0 to 18 years (N = 60).*

Age Range (y)

0-2 3-6 7-12 13-18 Total Outcome (n = 3) (n = 18) (n = 12) (n -- 27) (N = 60)

Death 1 2 0 4 7 Sequelae 0 0 1 3 4

*Six of seven deaths and all sequelae within 6 months of onset of use based on analysis of cases in the US Food and Drug Administration Adverse Event Reporting System as of August 6, 1999.

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Table VI. Labeling and pediatric exclusivity: Uncovering safety and efficacy issues.

Product Physicians' Desk (Date) New Safety or Dosing Information Reference ~, 200043

Midazolam Children with congenital heart disease (10/15/98) and pulmonary hypertension at

higher risk for adverse events; need to start at the lowest end of dosing range and titrate upward

Etodolac For efficacy: higher dose on mg/kg Safety and efficacy not (8/11/00) basis; difference in volume of established in pediatric

distribution and terminal half-life in patients younger children leads to mg/kg dosing 2 to 3 times higher than the lower dose in adults

Adolescents need higher doses, girls 8 to 11 years may require lower doses (nonlinear pharmacokinetics)

Fluvoxamine (9•28•00)

Gabapentin (10/12•00)

Loratadine (12/4/00)

Propofol (2/23/01)

Children younger than 5 years require higher doses (oral clearance normalizes as body weight increases); increased aggressiveness noted in pediatric patients compared with controls

Pharmacokinetic parameters in children aged 2 to 5 years given a 5-mg dose were comparable to those in children aged 6 years to adolescence given a 10-rag dose

Serious bradycardia may occur when administered with fentanyl; with prolonged infusion, abrupt discontinuation may result in increased irritability and flushing; 20 (9%) of 222 pediatric patients treated in the propofol arm for intensive-care unit sedation experienced a higher mortality compared with 4 (4%) of 105 patients treated with other sedatives (causality not established)

Already includes the precaution to start at 0.25 mg/kg (lower dose)

Prominent effect noted in children aged 8 to 11 years; essentially no effect in children aged 12 to 17 years

Safety and efficacy below age 12 years not established

Safety and effectiveness have not been established under 6 years of age

Not recommended for pediatric patients in intensive-care units or during monitored anesthesia care (MAC) sedation

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receiving loratadine needed one half the dose required by patients aged 6 to adolescence. Adolescents receiving fluvoxamine needed higher doses, whereas girls aged 8 to 11 years may require lower doses than originally recommended. A higher number of deaths was noted in patients receiving propofol for sedation in the intensive-care units (ICUs) compared with controls. The causality has not been determined. Of interest, the postmarketing data on propofol available through MedWatch examined 261 reports in patients 0 to 16 years of age. Of 261 adverse events, 58 fatalities occurred (44 cases after review of the reports and elimination of duplicates), 25 of which were in ICU sedation. Hence, the spontaneous reporting system and the formal study seem to agree regarding concern about serious adverse events in the ICU.

CONCLUSIONS Exposure to any medications can result in adverse events. Some of these events are predictable or preventable, whereas others are idiosyncratic. Adverse events can also occur with long-term exposure to a drug, such as drug depen- dence (eg, benzodiazepines), effect on the HPA axis of a child after long-term exposure to steroids, or unpredicted carcinogenic or teratogenic effects. Medi- cation errors as well as unexpected effects of long-term exposure constitute other causes of adverse events in the pediatric population. In addition, adverse events may be delayed or never identified in the pediatric population because no adult equivalent of the adverse event exists (ie, it is unique to the evolving physiology of childhood). Inappropriate dosing while using products off label, which results in either over- or undermedication, should be considered as an additional adverse event category.

With the current initiative driving pediatric studies, adverse events caused by improper dosing should be preventable. Predicting outcomes and side effects from the adult experience may not always be possible, as demonstrated by the examples described in this report. The inherent differences between pediatric and adult patients demand a focused approach to drug assessment in the pediatric population. The benefits of such an approach include not only safe but evidence-based, rational use in this population.

ACKNOWLEDGMENTS The Workshop on Adverse Drug Events in Pediatrics was sponsored by the National Institute of Child Health and Human Development, the US Food and Drug Administration, the Agency for Healthcare Research and Quality, and the United States Pharmacopeia.

The authors thank the pharmacology/toxicology working group for their contribution to the preclinical information section. The views expressed are those of the authors. No official support or endorsement by the US Food and Drug Administration is provided or should be inferred. No commercial interest

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or o the r conflict of in teres t exis ts be t ween the au tho r s and the m a n u f a c t u r e r s of the p roduc t s .

REFERENCES 1. Shirkey H. Therapeutic orphans. Pediatrics. 1999;104(Pt 2):583-584. 2. US Food and Drug Administration. Milestones in US Food and Drug Law History-FDA

Backgrounder. Current and Useful Information from the Food and Drug Administration. Available at: http://www.fda.gov/opacom/backgrounders/miles.html. Accessed: May 3, 1999.

3. US Food and Drug Administration. Class labeling for intranasal and orally inhaled corticosteroid containing drug products regarding the potential for growth suppression in children. Division of Pulmonary Drug Products. Rockville, Md: US Food and Drug Administration; November 9, 1998. Talk Paper. Available at: http://www.fda. gov/cder/news/cs_label.htm.

4. Kaushal R, Bates DW, Landrigan C, et al. Medication errors and adverse drug events in pediatric inpatients. JAMA. 2001;285:2114-2120.

5. Rici D, Barone S Jr. Critical periods of vulnerabilities for the developing nervous systems: Evidence from human and animal models. Environ Health Perspect. 2000;108(Suppl 3):511-533.

6. Radde IC. Mechanisms of drug absorption and their development. In: Macleod SM, Radde IC, eds. Textbook of Pediatric Clinical Pharmacology. Littleton, Mass: PSG Pub- lishing Co; 1985:17--43.

7. Burry P. Structural aspects of prenatal and postnatal development and growth of the lung. In: McDonald JA, ed. Lung Growth and Development. New York: Marcel Dekker Inc; 1997:1-35.

8. Knowles SR, Uetrecht J, Shear NH. Idiosyncratic drug reactions: The reactive me- tabolite syndromes. Lancet. 2000;356:1587-1591.

9. Gruchalla RS. Clinical assessment of drug-induced disease. Lancet. 2000;356:1505-1511. 10. Farwell JR, Lee Y J, Hirtz DG, et al. Phenobarbital for febrile seizuresmEffects on

intelligence and on seizure recurrence. N Engl J Med. 1990;322:364-369. 11. Baldessarini RJ. Drugs and their treatment of psychiatric disorders. In: Goodman A,

Rail T, Nies A, Taylor P, eds. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 8th ed. New York: McGraw-Hill; 1990:383--435.

12. Yokoyama H, Onodera K, Yagi T, linuma K. Therapeutic doses of theophylline exert proconvulsant effects in developing mice. Brain Dev. 1997;19:403--407.

13. Sande MA, Mandell GL. Antimicrobial agents. In: Goodman A, Rail T, Nies A, Taylor P, eds. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 8th ed. New York: McGraw-Hill; 1990:1117-1145.

14. Hiller JL, Benda G J, Rahatzad M, et al. Benzyl alcohol toxicity: Impact on mortality and intraventricular hemorrhage among very low birth weight infants. Pediatrics. 1986;77:500-506.

15. Ellenhorn M, ed. Alcohols and glycols. Benzyl alcohol clinical presentation. In: El- lenhorn M, Schonwald S, Ordog G, Wassenberg J, eds. Ellenhorn's Medical Toxicology. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:1127-1165.

16. Jawetz E. Chloramphenicol and tetracycline. In: Katzing Bertran G, ed. Basic and Clinical Pharmacology. 6th ed. Norwalk, Conn: Appleton & Lange; 1995:693-698.

17. Insel PA. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, Goodman-Gilman A, Limbird LE, eds. Good- man and Gilman's: The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:617-658.

721


18. Haughey DB, Hilligoss DM, Grassi A, Schentag JJ. Two-compartment gentamicin pharmacokinetics in premature neonates: A comparison to adults with decreased glomerular filtration rates. J Pediatr. 1980;96:325-330.

19. Heimann G. Renal toxicity of aminoglycosides in the neonatal period. Pediatr Pharmacol. 1983;3:251-257.

20. Stahlman R, Chahoud S, Thiel R, et al. The developmental toxicity of three antimicrobial agents observed only in nonroutine animal studies. Reprod Toxicol. 1997; 11: 1-7.

21. Towfighi J. Hexachlorophene. In: Spencer P, Scaumberg H, eds. Experimental and Clinical Neurotoxicology. Baltimore, Md: Williams & Wilkins; 1980:440-445.

22. Belay ED, Breese JS, Hoiman RC, et al. Reye's syndrome in the United States from 1981 through 1987. N Engl J Med. 1999;340:1377-1382.

23. Ellenhorn M, ed. Systematic toxicology. Antiarrhythmics drug class IV calcium chan- nel blockers. In: Ellenhorn M, Schonwald S, Ordog G, Wassenberg J, eds. Ellenhorn's Medical Toxicology. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:498-550.

24. Skovranek J, Ostadtal B, Pelouch V, Prochazka J. Ontogenetic differences in cardiac sensitivity to verapamil in rats. Pediatr Cardiol. 1986;7:25-29.

25. Daunorubicin hydrochloride. In: Schefer J, ed. 2001 Mosby's GenRx~-The Complete Reference for Generic and Brand Drugs. 1 lth ed. St. Louis: CV Mosby Co; 2001:437- 438.

26. Ellenhorn M, ed. Systemic toxicology. The antihypertensive drugs. In: Ellenhorn M, Schonwald S, Ordog G, Wassenberg J, eds. Ellenhorn's Medical Toxicology. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:551-568.

27. Ellenhorn M, ed. Over-the-counter products and drug interactions: The retinoids. In: Ellenhorn M, Schonwald S, Ordog G, Wassenberg J, eds. Ellenhorn's Medical Toxicol- ogy. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:971-1035.

28. Novak LL. Attention deficit hyperactivity disorder. In: Dambro MR, Griffith JA, eds. Griffith's 5 Minute Clinical Consult 2001. 9th ed. Lippincott Williams & Wilkins. STAT!Ref Electronic Medical Library. Accessed: February 24, 2001.

29. DuMouchel W. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system. Am Statistician. 1999;53:177-190.

30. O'Neill RT, Szarfman A. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system, by William DuMouchel. Am Statistician. 1999;53:190-196. Discussion.

31. Louis TA, Shen W. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system, by William DuMouchel. Am Statisti- cian. 1999;53:196-198. Discussion.

32. Madigan D. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system, by William DuMouchel. Am Statistician. 1999; 53:198-200. Discussion.

33. DuMouchel W. Bayesian data mining in large frequency tables, with an application to the FDA spontaneous reporting system, by William DuMouchel. Am Statistician. 1999;53:201-202. Reply.

34. Szarfman A. The application of Bayesian data mining and graphic visualization tools to screen FDA's spontaneous reporting system database. 2000 Proceedings of the Section on Bayesian Statistical Science, American Statistical Association, pp 67-71.

35. DuMouchel W, Pregibon D. Empirical Bayes screening for multi-item associations. Proceedings of the International Conference on Knowledge Discovery and Data Min- ing, San Francisco, California, August 26-29, 2001. ACM Press; 2001:67-76.

722

W. Rodriguez et oL

36. Szarfman A, Talarico L, Levine JG. Analysis and risk assessment of hematological data from clinical trials. In: Sipes IG, McQueen CA, Gandolfi A J, eds. Comprehensive Toxicology. New York: Elsevier Science Inc; 1997:363-379.

37. Szarfman A. Discussion: A report on the activities of the adverse events working groups: Focus on improving the detection of rare but serious adverse events. 1999 Proceedings of the Biopharmaceutical Section, American Statistical Association, pp 12-14.

38. O'Neill RT, Szarfman A. Some US Food and Drug Administration perspectives on data mining for pediatric safety assessment. Curr Ther Res Clin Exp. 2001;62:650-663.

39. MedWatch" The FDA Safety Information and Adverse Event Reporting Program. Available at: http://www.fda.gov/medwatch. Accessed: May 10, 1999. FDA Report.

40. Department of Health and Human Services. Fed Register. 2000;65:81082-81131 (codi- fied at 21 CFR 201).

41. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: A retrospec- tive review. Neurology. 1987;37:379-385.

42. US Food and Drug Administration Modernization Act of 1997, Section 505A of the Federal Food, Drug and Cosmetic Act, 21 USC 355a (1997).

43. Physicians' Desk Reference ®. 54th ed. Montvale, N J: Medical Economics Company; 2000.

Address correspondence to: William Rodriguez, MD Science Direc tor for Pedia t r ics DHHS/FDA/CDER/ORM/ODE IV 9201 C o r p o r a t e Boulevard, HFD-104 Rockville, MD 20850 E-mail: Rodr iguezw@cder . fda .gov

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adverse drug events in children: the us food and drug administration perspective

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