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Original Contribution |

Pediatric Drug Labeling:  Improving the Safety and Efficacy of Pediatric Therapies FREE

Rosemary Roberts, MD; William Rodriguez, MD; Dianne Murphy, MD; Terrie Crescenzi, RPh
[+] Author Affiliations

Author Affiliations: Office of Counter-Terrorism and Pediatric Drug Development, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Md.


JAMA. 2003;290(7):905-911. doi:10.1001/jama.290.7.905.
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Context Approximately 50% to 75% of drugs used in pediatric medicine have not been studied adequately to provide appropriate labeling information. In 1997, Congress passed the Food and Drug Administration Modernization Act (FDAMA), which encouraged pediatric drug development by providing an incentive in the form of additional marketing exclusivity.

Objective To identify new drug labeling information from pediatric studies submitted to the FDA in response to written requests.

Design and Setting Between July 1998 and April 1, 2002, the FDA requested studies on 242 drugs, and 53 drugs were granted exclusivity. As of January 2003, 49 drugs have new labels. Data from the studies of the first 33 drugs with new pediatric information on the label as of April 2002 are included. Significant labeling information was analyzed along with baseline data and types of studies requested.

Main Outcome Measures Safety data and pediatric information for labeled drugs.

Results There were 53 studies for 33 drug products, 12 (23%) were evaluated for safety only; 23 (43%), safety and efficacy; and 18 (34%), pharmacokinetics and/or pharmacodynamics. Significant new dosing and/or safety information was identified for 12 (36%) drugs. New dosing information was determined for 7 of these drugs. Safety information was defined for gabapentin, propofol, sevoflurane, the combination of ribavirin and interferon alfa-2b, and various betamethasone-containing dermatologic preparations. There was a higher percentage of deaths reported with patients who received propofol compared with controls in the pediatric intensive care unit. Seizures were seen in patients administered sevoflurane. Patients receiving a combination of ribavirin and interferon alfa-2b experienced an increased incidence of suicidal ideation when compared with adults. An unexpectedly high percentage of those receiving betamethasone-containing dermatologic preparations had documented hypopituitary-adrenal axis suppression.

Conclusion The FDAMA has stimulated pediatric clinical studies resulting in improved understanding of the pharmacokinetics of drugs prescribed in pediatric medicine, important dose changes, and improved safety for children taking certain drugs.

The phrase "therapeutic orphan" was used to describe children in 1963 by Harry Shirkey, MD.1 There had been little stimulus for pharmaceutical companies to study drugs in children because of the complexity of such trials and the small financial return. Furthermore, the assumption that children with diseases or conditions similar to adults respond similarly has perpetuated the use of medications approved in adults to treat children, frequently without the appropriate studies in the pediatric population. Forty years later, only one third of drugs used to treat children have been studied adequately in the population in which they are being used and have appropriate use information on the product label.2 For the other two thirds of drugs, information regarding safety and efficacy for pediatric patients is insufficient or absent. The younger the age group, the more likely the lack of information.3

As a result, pediatricians and other health care professionals who treat children have had to use these drugs on a trial and error basis. Furthermore, information on the drug's efficacy and safety is not methodically collected and analyzed. Prescribing medications to children that have not been labeled for their use is termed off-label use —outside of the terms of the product approval.4 Off-label use may result in benefit, no therapeutic effect, or harm (adverse reactions). A lack of efficacy may be the result of underdosing, while adverse effects may result from a failure to understand the impact of developmental, physiological, or metabolic influences on a drug's pharmacokinetics.5

Pediatric patients may also be deprived of potentially effective medication because of the prescriber's reluctance to use a medication for an off-label use. Off-label use in pediatrics affects both seriously ill hospitalized patients and the millions of children treated outside the hospital for symptomatic illness. The problem of off-label use of drugs in pediatrics is international and affects pediatric patients in the United States, Europe, Asia, Africa, and South America.4,68 Hence, initiatives to encourage and promote pediatric labeling for drugs to provide the needed information to use them safely and efficaciously in the pediatric population have become a prime concern for legislative and regulatory bodies. The ongoing initiatives in the United States have been perceived as beneficial and a sign of leadership in public health by caregivers in other areas of the world.4

Well-controlled studies involving children have been encouraged for many years.9 The Food and Drug Administration (FDA) in 1994 spelled out scenarios that would allow establishing pediatric claims. These included extrapolating efficacy data from adequate and well-controlled studies in adults in which the course of the disease or condition and the drug's effects are sufficiently similar between adults and children. To support such a claim, pharmacokinetic studies to allow determination of an appropriate pediatric dose and safety studies are necessary; it may not be necessary to repeat the efficacy studies for certain drugs.10

The Food and Drug Administration Modernization Act (FDAMA) was signed into law on November 21, 1997. The FDAMA encourages studies of certain therapies being used in pediatrics by providing an exclusivity incentive provision. This provision provides an additional 6 months of marketing exclusivity (ie, no generics can be approved), if the sponsor voluntarily conducts the studies requested by FDA in the written request, submits them in the specified time frame, and the studies fairly respond to the written request. Under FDAMA, the FDA was mandated to develop, prioritize, and publish a list of approved drugs used off label and for which information on how to use the drugs in the pediatric population was needed. The initial working list comprised recommendations from the American Academy of Pediatrics, the Pharmaceutical Research Manufacturers Association, the National Institutes of Health, the Pediatric Pharmacology Research Units Network, the National Pharmaceutical Alliance, the Generic Pharmaceutical Industry Association, the National Association of Pharmaceutical Manufacturers, and the United States Pharmacopeia. Most written requests issued by the FDA have been for drugs on this list.

This incentive has been a driving force stimulating the conduct of pediatric studies. The pediatric labeling process in the United States progressed from encouraging the pharmaceutical industry to conduct pediatric studies in the 1980s and 1990s to a combined approach of the FDAMA's voluntary incentives (1997) and mandatory regulation (1998; Pediatric Rule).11 The FDAMA exclusivity legislation should not be confused with the Pediatric Rule. The latter required pediatric studies for those conditions being studied in adults and in which significant use or benefit in pediatrics was expected. As of October 17, 2002, the US District Court for the District of Columbia enjoined the FDA from enforcing the Pediatric Rule.

Marketing exclusivity has been a driving force stimulating the conduct of pediatric studies. To examine the health benefits that were derived from the pediatric studies linked to the exclusivity incentives, we analyzed the resulting new labeling changes between July 1998 and April 2002. The Best Pharmaceuticals for Children Act,12 enacted January 4, 2002, renews the pediatric exclusivity provision. Our aim is to provide information supported by evidence available to and reviewed by the FDA that has been submitted in response to written requests and has resulted in new pediatric information on the label.

We identified new labeling information from all drugs in the referenced time frame that received approved pediatric labeling under the FDAMA exclusivity program. The pediatric studies asked for by the FDA were outlined in written requests issued by the FDA to the pharmaceutical companies. The results of the studies were submitted by the pharmaceutical companies with a request for an exclusivity determination. The responsible regulatory division(s) reviewed the data and negotiated the new labeling information with the pharmaceutical company. We examined the types of studies and the data submitted that resulted in new labeling information. For the purpose of this article, we have defined off-label use as use outside of the FDA-approved label. Pediatric studies are defined as representing at least 1 clinical investigation, which could include pharmacokinetic studies, in the pediatric age groups in which the drug was anticipated to be used.13 We divided the new labeling information into 2 groups: those active moieties with new adverse events or dosing information defined as significant (Table 1); and those active moieties for which information led to approval of their use in pediatric subpopulations (Table 2). We also examined non-FDA source data for pediatric information on safety and dosing recommendations available to prescribers for these products from 2 reference sources.14,15

Table Graphic Jump LocationTable 1a. Characteristics and Indications of Drug Products With Significant Changes or Findings
Table Graphic Jump LocationTable 2. Pediatric Labeling Changes for Additional Drug Products Studied Under the Pediatric Exclusivity Program

Between July 1998 and April 2002, 53 drugs were granted pediatric exclusivity and 33 drug products have new labels with pediatric information. This information was derived from the 53 studies conducted in response to written requests. The spectrum of use of these products indicates a wide array of pediatric conditions such as fever and pain, sedation and anxiety, gastroesophageal reflux, allergic conditions (rhinitis, conjunctivitis, urticaria), diabetes, xerosis/ichthyosis, juvenile rheumatoid arthritis, human immunodeficiency virus infection, obsessive-compulsive disorder, hypertension, cholesterol management, anesthesia, and seizures. The 33 drugs and the new pediatric information about each drug are listed in Table 1 and Table 2.

A total of 50 482 patients participated in the 53 studies that provided the information for new labeling. This includes the 41 356 patients (aged 6 months to 2 years) who participated in 2 large safety (actual use) studies of ibuprofen over-the-counter products. The remaining 31 products involved 9126 patients. The types of studies conducted were as follows: safety only, 12 (23%); safety and efficacy, 23 (43%); and pharmacokinetic and pharmacodynamic, 18 (34%). Safety data were collected in all studies. New data for the 33 drug products were provided for the following specified ages: neonates, 7 (21%); 1 month to 3 years, 11 (33%); older than 3 years to 6 years, 20 (61%); and older than 6 years to 12 years, 24 (73%). Studies in 21 (64%) of 33 drug products included adolescent patients older than 12 years and younger than 17 years. Thirty-two labels lowered the age in the pediatric population for which there was information on how to use the product.

For 12 (36%) of these products, the data obtained resulted in knowledge that has improved understanding of the specific drug based on pharmacokinetics or safety information (adverse events). Of the 12 labels with highly important new information, 7 (58%) were relevant to dosing and had new safety information. For 2 (sotalol hydrochloride and the combination of ribavirin and interferon alfa-2b) of the 12 drugs, significant safety information was obtained, although efficacy was not demonstrated. For buspirone hydrochloride, there was a failure to demonstrate efficacy (Table 1).

The important dosing information defined for 7 (21%) of 33 drug products demonstrates the value of conducting pharmacokinetic or pharmacodynamic studies in the pediatric population (Box). The benefits and information provided through labeling in the 20 other drugs are shown in Table 2. Generally speaking, the benefits included enhancement of the understanding of the safety and the pharmacokinetic profile of the drugs down to the age specified. Of note, there is no need to increase the dose of loratadine in children aged 2 to 5 years. Instead, the pharmacokinetic profile shows that these patients should receive half the dose compared with children aged 6 to 12 years.

Box Section Ref IDBox. Newly Revised Dosing and Safety Information

Dosing

  • Midazolam hydrochloride (Versed): Information demonstrated a need to modify the approach to dosing for a vulnerable group of children (ie, patients with congenital heart disease and pulmonary hypertension).

  • Fluvoxamine maleate (Luvox): Dose adjustments for pediatric patients were necessary to obtain a therapeutic effect and to minimize adverse events. The previous label reported a prominent treatment effect in patients aged 8 to 11 years and essentially no effect in patients aged 12 to 17 years.14

  • Gabapentin (Neurontin): Dosing for patients aged 3 to 12 years was defined based on the pharmacokinetic parameters measured. A higher oral clearance was noted when normalized by body weight in patients 5 years or younger. Neuropsychiatric adverse events were noted as a significant adverse effect more often in those treated than in the controls.

  • Etodolac (Lodine): Now indicated for treatment of the signs and symptoms of juvenile rheumatoid arthritis in patients aged 6 to 16 years. The pharmacokinetic information demonstrated that the volume of distribution for pediatric patients was different from adults. A higher dose is recommended for younger children.

  • Sotalol hydrochloride (Betapace): Individualized dosing should be on a milligram per meter squared basis particularly for patients with a body surface area of less than 0.33 m2 in which increased corrected QT interval effects were seen.

  • Buspirone hydrochloride (Buspar): Despite pharmacokinetic parameters (area under the curve and maximum concentration of drug) of buspirone and its active metabolite, which were equal to or exceeded the adult levels, safety and effectiveness were not established for generalized anxiety disorder.

  • Atovaquone and proguanil hydrochloride (Malarone): New pediatric information on the safety and efficacy in prophylaxis and treatment of malaria were shown, as well as pharmacokinetic differences between the pediatric and adult populations.

Safety Information

  • Ribavirin and interferon alfa-2b (Rebetron): Neuropsychiatric and generally reversible growth adverse events were identified for pediatric patients receiving the combination of ribavirin and interferon alfa-2b.

  • Pimecrolimus (Elidel): Labeling with the original approval identified safety concerns (eg, increase in infections, pyrexia, and diarrhea in patients younger than 2 years).

  • Betamethasone (Diprolene, Diprosone, Lotrisone): Topical betamethasone-containing dermatologic products were associated with a suppression of the hypopituitary-adrenal axis in 28% to 75% of the pediatric patients depending on the age of the patient and product used.

  • Propofol (Diprivan): Studies allowed the indication for maintenance of anesthesia to be lowered to patients aged 2 months or older, but raised concerns about its use for sedation in the pediatric intensive care unit. Serious adverse events were identified when drug was administered with fentanyl.

  • Sevoflurane (Ultane): Studies have established the safe and effective use as an anesthetic to age 1 month, as well as a new precaution about rare cases of seizures noted in children and young adults.

Within a year of FDA label approval, data for 11 (33%) of the drug products had already been incorporated in sources available to those who prescribe medications for pediatric patients. Of the 33 drug products, 6 (18%) were new molecular entities for which pediatric labeling became available at the time of the original new drug application approval. The information provided herein is now available to pediatricians and may be different from the information currently available from readily accessible sources.14,15 An important benefit of this initiative has been the development of new commercially available formulations in 5 (15%) products to facilitate pediatric use (abacavir sulfate, midazolam hydrochloride, gabapentin, ibuprofen/pseudoephedrine hydrochloride, and atovaquone and proguanil hydrochloride). Additionally, a recipe for an extemporaneous formulation was evaluated and included on the label for 2 of the drugs (enalapril maleate and sotalol hydrochloride).

In 1996, a committee of the American Academy of Pediatrics reported 17 drugs with widespread use in children and lack of appropriate drug labeling information.2 One of these products is no longer marketed. Of the 16 remaining drugs, 3 (19%) have had the requested studies conducted and the results have been submitted to the FDA. These 3 drugs now have new pediatric labeling (gabapentin, fluoxetine hydrochloride, and midazolam hydrochloride). These labels include information critical to understanding the safety and efficacy of these drugs.

Of the first 33 labeled drug products, observations for 7 (21%) led to major adjustments in the dosing instructions. With the information obtained from the pharmacokinetic and/or pharmacodynamic studies, the labels now contain appropriate dosage information for the pediatric population. For other drugs, the labels contain special precautions about use in a specific setting (eg, propofol and the risk for severe adverse events in the pediatric intensive care unit, rare cases of seizures associated with sevoflurane, suicidal ideation noted in some patients receiving a combination of ribavirin and interferon alfa-2b, and hypopituitary-adrenal axis suppression with betamethasone-containing dermatologic products).

Studies continue to be submitted and the number of drugs with pediatric use information on the labels continues to increase. As of January 2003, 16 more drugs have been labeled with pediatric use information, which brings the total to 49 new labels.

These pediatric initiatives are expected to have worldwide effects and benefit all children. A report by ‘t Jong et al4 on off-label use of drugs in the Children's Hospital in the Netherlands found that of 238 children and adolescents from birth to age 17 years, only 725 (34%) of the 2139 prescriptions they received were for uses approved on the label. Of the remaining 66%, 1024 (48%) were unapproved and 390 (18%) were for off-label use. McIntyre et al16 examined 3347 prescriptions for 1175 children in the English midlands and 160 different drugs. Approximately 11% of the prescriptions deviated from licensed use. The same investigators found that of 455 prescriptions for 70 neonates, only 161 (35%) of the prescriptions "were licensed drugs used in a licensed way."17

The off-label ("outside the terms of their license") or unlicensed ("not specifically licensed for use in children") use of medications is also reported by Gravilov et al7 from an ambulatory hospital unit in Israel. The authors reported approximately 42% of drug prescriptions to children were for off-label and/or unlicensed use. A survey of off-label drug use was also performed in 5 European countries.18 Of 624 pediatric patients in 5 hospitals who received 2262 prescriptions, 1036 (46%) prescriptions were for unlicensed or off-label use; 421 (67%) patients received drugs for an unlicensed or off-label use. The problem is more acute in neonatal units. Avenel et al8 reported an experience in which 62% of drug use was for off-label indications for premature infants and 64% for off-label indications for newborns. Unfortunately, there were no therapeutic alternatives among the few available licensed drugs.

The recent policy changes in the United States, which have resulted in increased numbers of studies of the drugs being prescribed to children, have been called for internationally by others.4,19 Drugs used in children should be studied in accordance with sound ethical and scientific principles to define differences in efficacy, age-dependent changes in pharmacokinetics and/or pharmacodynamics, and to identify unique pediatric adverse events, as well as verify the adverse events that are similar to those experienced by adults.20 Steinbrook's21 recent report including some of the benefits derived from the exclusivity incentive supports our observation. The beneficial effects of studying drugs that are being prescribed to children include important dose changes, as well as improved safety information on how to more appropriately prescribe these drugs for the pediatric population.

Shirkey H. Editorial comment: therapeutic orphans.  J Pediatr.1968;72:119-120.
Cote C, Kaufmann R, Troendle G, Lambert H. Is the "therapeutic orphan" about to be adopted?  Pediatrics.1996;98:118-123.
PubMed
US Food and Drug Administration.  Pediatric Exclusivity Provision: Status Report to Congress. Rockville, Md: Food and Drug Administration; 2001.
‘t Jong WT, Vulto A, DeHoog M, Schimmel KJ, Tibboel D, Van den Anker JN. Unapproved and off label use of drugs in a children's hospital.  N Engl J Med.2000;343:1125.
Rodriguez W, Roberts R, Murphy D. Adverse drug events in children: the US Food and Drug Administration perspective.  Curr Ther Res.2001;62:711-723.
Committee on Drugs.  Unapproved uses of approved drugs: the physician, the package insert, and the Food and Drug Administration: subject review.  Pediatrics.1996;98:143-145.
PubMed
Gravilov V, Lifskitz M, Levy J, Gorodischer R. Unlicensed and "off label" medication use in a general pediatrics ambulatory hospital unit in Israel.  Isr Med Assoc J.2000;2:595-597.
PubMed
Avenel S, Bomkratz A, Dassieu G, Janaud JC, Danan C. The incidence of prescriptions without marketing product license in a neonatal intensive care unit.  Arch Pediatr.2000;7:143-147.
 Labeling and prescription drug advertising: content and format for labeling for human prescription drugs.  44 Federal Register.37434 (1979).
 Specific requirements on content and format of labeling for human prescription drugs: revision of "pediatric use" subsection in the labeling.  59 Federal Register.64240 (1994).
 Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients.  63 Federal Register.66631 (1998).
 Best Pharmaceuticals for Children Act. Pub L No. 107-109.
US Food and Drug Administration.  Guidance for Industry: Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug and Cosmetic Act. Rockville, Md: Food and Drug Administration; 1999.
 Physicians' Desk Reference . 54th ed. Montvale, NJ: Medical Economics Co Inc; 2000.
Siberry GK, Iannani R. Harriett Lane Handbook. 15th ed. St Louis, Mo: Mosby Inc; 2000.
McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and "off label" prescribing of drugs in general practice.  Arch Dis Child.2000;83:498-501.
PubMed
Conroy S, McIntyre J, Choonara I. Unlicensed and "off label" drug use in neonates.  Arch Dis Child Fetal Neonatal Ed.1999;80:F142-F145.
PubMed
Conroy S, Choonara I, Impicciatore P.  et al.  Survey of unlicensed and "off label" drug use in pediatric wards in European countries.  BMJ.2000;320:79-82.
PubMed
International Conference on Harmonisation.  Guidance on E11 clinical investigation of medicinal products in the pediatric population.  65 Federal Register.78493 (2000).
Conroy S, McIntyre J, Choonara I. Unlicensed and off label use in neonates [reply letter].  Arch Dis Child Fetal Neonatal Ed.2000;82:F77.
Steinbrook R. Testing medications in children.  N Engl J Med.2002;347:1462-1470.
PubMed

Figures

Tables

Table Graphic Jump LocationTable 1a. Characteristics and Indications of Drug Products With Significant Changes or Findings
Table Graphic Jump LocationTable 2. Pediatric Labeling Changes for Additional Drug Products Studied Under the Pediatric Exclusivity Program

References

Shirkey H. Editorial comment: therapeutic orphans.  J Pediatr.1968;72:119-120.
Cote C, Kaufmann R, Troendle G, Lambert H. Is the "therapeutic orphan" about to be adopted?  Pediatrics.1996;98:118-123.
PubMed
US Food and Drug Administration.  Pediatric Exclusivity Provision: Status Report to Congress. Rockville, Md: Food and Drug Administration; 2001.
‘t Jong WT, Vulto A, DeHoog M, Schimmel KJ, Tibboel D, Van den Anker JN. Unapproved and off label use of drugs in a children's hospital.  N Engl J Med.2000;343:1125.
Rodriguez W, Roberts R, Murphy D. Adverse drug events in children: the US Food and Drug Administration perspective.  Curr Ther Res.2001;62:711-723.
Committee on Drugs.  Unapproved uses of approved drugs: the physician, the package insert, and the Food and Drug Administration: subject review.  Pediatrics.1996;98:143-145.
PubMed
Gravilov V, Lifskitz M, Levy J, Gorodischer R. Unlicensed and "off label" medication use in a general pediatrics ambulatory hospital unit in Israel.  Isr Med Assoc J.2000;2:595-597.
PubMed
Avenel S, Bomkratz A, Dassieu G, Janaud JC, Danan C. The incidence of prescriptions without marketing product license in a neonatal intensive care unit.  Arch Pediatr.2000;7:143-147.
 Labeling and prescription drug advertising: content and format for labeling for human prescription drugs.  44 Federal Register.37434 (1979).
 Specific requirements on content and format of labeling for human prescription drugs: revision of "pediatric use" subsection in the labeling.  59 Federal Register.64240 (1994).
 Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients.  63 Federal Register.66631 (1998).
 Best Pharmaceuticals for Children Act. Pub L No. 107-109.
US Food and Drug Administration.  Guidance for Industry: Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug and Cosmetic Act. Rockville, Md: Food and Drug Administration; 1999.
 Physicians' Desk Reference . 54th ed. Montvale, NJ: Medical Economics Co Inc; 2000.
Siberry GK, Iannani R. Harriett Lane Handbook. 15th ed. St Louis, Mo: Mosby Inc; 2000.
McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and "off label" prescribing of drugs in general practice.  Arch Dis Child.2000;83:498-501.
PubMed
Conroy S, McIntyre J, Choonara I. Unlicensed and "off label" drug use in neonates.  Arch Dis Child Fetal Neonatal Ed.1999;80:F142-F145.
PubMed
Conroy S, Choonara I, Impicciatore P.  et al.  Survey of unlicensed and "off label" drug use in pediatric wards in European countries.  BMJ.2000;320:79-82.
PubMed
International Conference on Harmonisation.  Guidance on E11 clinical investigation of medicinal products in the pediatric population.  65 Federal Register.78493 (2000).
Conroy S, McIntyre J, Choonara I. Unlicensed and off label use in neonates [reply letter].  Arch Dis Child Fetal Neonatal Ed.2000;82:F77.
Steinbrook R. Testing medications in children.  N Engl J Med.2002;347:1462-1470.
PubMed
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