Recent Revisions in Drug Labeling for Children

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2004;10(3) 

In February, the Food and Drug Administration (FDA) updated its listing of pediatric labeling changes resulting from the Pediatric Exclusivity Program.[1] The program, which allows the FDA to grant an additional six months of marketing exclusivity to manufacturers submitting pediatric data, was developed as part of the FDA Modernization Act of 1997.[2] Since 1999, when the program became active, pediatric data have been evaluated for 101 medications, with 86 granted first-time exclusivity and five granted a second period. Based on the data submitted, changes are made in the product labeling, including all product information inserts, advertisements, and promotional materials. This issue of Pediatric Pharmacotherapy will review the labeling changes approved during the period from January 2003 to January 2004.

Based on the FDA approval granted in January 2004, product labeling for the calcium channel blocker amlodipine (Norvasc®; Pfizer) will now include information on dosing and pharmacokinetics in children ages 6 to 17 years. The recommended dosage range for children is 2.5 to 5 mg given once daily. In addition, labeling will indicate that the adverse effect profile observed in children is similar to that established in adults.

The combination of atovaquone and proguanil (Malarone®; GlaxoSmithKline) will now include a statement that safety and efficacy for the treatment of malaria have been established down to patients weighing 5 kg. In pediatric patients, the most frequent adverse effect in clinical trials was diarrhea (6%). The apparent drug clearances (CL/F) of both atovaquone and proguanil were related to weight in the pediatric studies. As a result, dosing recommendations are weight-based for patients weighing less than 40 kg. New labeling, as of December 2003, will also include instructions to crush the tablets and mix with condensed milk for children unable to swallow whole tablets.

Budesonide (Pulmicort® Respules; AstraZeneca) is now labeled with safety information in pediatric patients with asthma as young as 6 months of age. In addition, adverse effect information will include results from a 12-week trial in infants 6 to 12 months of age which suggested that budesonide produces a dosedependent effect on growth similar to that observed in studies of other inhaled corticosteroids. Pneumonia has also been observed more frequently in pediatric patients treated with budesonide than placebo.

Pharmacokinetic data from an open-label study in 24 infants and children has been incorporated into the product labeling for busulfan (Busulfex®; Orphan Medical). The children, ranging in age from 5 months and 16 years, were given busulfan as part of a conditioning regimen administered prior to stem cell transplantation. Based on the results of this study, a suggested dosing regimen has been developed.

Transdermal fentanyl (Duragesic®; Alza) labeling will now indicate that it may be used in children ages 2 years and older with chronic pain who are opioid-tolerant. The safety of the transdermal system was evaluated in three open-label trials which enrolled a total of 291 children with chronic pain who were between 2 and 18 years of age. Adverse effects in these trials included fever (35%), vomiting (33%), and nausea (24%). There were no pediatric-specific adverse effects. New pharmacokinetic, dosing, and administration information has also been added to the labeling, as well as patient information and a precaution to guard against accidental ingestion of the patches by children.

This labeling change represents a considerable advancement in the tools available for the management of chronic pain in young children. While many pediatric institutions have already been using the transdermal fentanyl preparation, the availability of standardized dosing recommendations should reduce the likelihood of medication errors. The new product information should be reviewed carefully to ensure appropriate conversion from intravenous or oral opioids to the transdermal system.

Labeling for fexofenadine (Allegra®; Aventis) was amended in May 2003 to include the results of three new pediatric studies. The trials provided safety and efficacy data from a total of 845 infants and children up to 5 years of age with allergic rhinitis.

Pediatric studies were conducted by the manufacturer of fludarabine (Fludara®; Berlex); unfortunately, data from the 62 children evaluated were insufficient to establish efficacy in childhood malignancies.

In January 2003, the labeling for fluoxetine (Prozac®; Lilly) was amended to state that effectiveness had been established in children 7 to 17 years of age with obsessive-compulsive disorder and in children 8 to 17 years of age with major depressive disorder. In addition, pediatric pharmacokinetic and adverse effect information was incorporated, as well as dosing recommendations. Additional adverse effect information includes data from a 19-week placebo-controlled trial of fluoxetine in pediatric patients in which treated patients gained an average of 1.1 cm less height and 1.1 kg less weight than controls. It is recommended that height and weight be monitored periodically in pediatric patients throughout treatment.

The approval of fluoxetine for children has been one of the more controversial labeling changes. While welcomed by health care providers caring for children who would benefit from the use of a selective serotonin reuptake inhibitor (SSRI), there has been concern over a possible link between other SSRIs and suicide in adolescents. This association is still being evaluated by the FDA, and further information is expected this year.

Data from a new 1-year, placebo-controlled trial in children (3 to 9 years of age) with allergic rhinitis receiving fluticasone nasal spray (Flonase®; GlaxoSmithKline) has been added to the product information. In this trial, no statistically significant adverse effect on growth was found with treatment. No evidence of clinically significant effects on HPA axis function or bone mineral density were observed.

Pediatric approval, however, was not granted for fluticasone ointment (Cutivate Ointment®; GlaxoSmithKline). This product is indicated in the management of corticosteroid-responsive dermatoses. In a study of 35 children with atopic dermatitis, subnormal adrenal function was observed with cosyntropin stimulation testing. Labeling will continue to state that Cutivate Ointment® is indicated for use only in adult patients.

Data from a double-blind study of fosinopril (Monopril®; Bristol-Myers Squibb), an angiotensin converting enzyme inhibitor used in the treatment of hypertension, have now been incorporated into the product labeling. The study was conducted in 252 children between 6 and 16 years. At this time, only dosing recommendations for children weighing greater than 50 kg will be included, as there is no lower dosage strength available for smaller patients.

Lisinopril (Prinivil®; Merck and Zestril®; AstraZeneca), another angiotensin converting enzyme inhibitor, will now be labeled for patients 6 to 16 years of age. Information on efficacy, pharmacokinetics, and dosing will be included for pediatrics. It is recommended that lisinopril not be used in children with a glomerular filtration rate < 30 ml/min/1.73m2. New product labeling will also include an extemporaneous formulation for preparing the drug as an oral liquid.

In April 2003, the labeling for the ophthalmic preparation of moxifloxacin (Vigamox®; Alcon) was changed to incorporate a statement that safety and effectiveness has been established in patients as young as 1 year of age. The ophthalmic moxifloxacin product is indicated for the treatment of bacterial conjunctivitis.

Orlistat (Xenical®; Roche), which is used to promote weight loss by blocking fat absorption, will now carry a statement that use in 12 to 16 year olds is supported by studies in adults and additional data from a 54-week safety and efficacy study conducted in obese adolescents. The adverse effects observed during this study were similar to those occurring in adults. Product labeling will also carry a recommendation that all patients taking orlistat take a daily multivitamin that contains fat-soluble vitamins.

Oxybutynin (Ditropan®; Johnson & Johnson) is currently approved by the FDA for use in children and adults with overactivity of the bladder detrusor muscle. In April 2003, product labeling was amended to include additional pediatric pharmacokinetic and dosing information. In addition, the extended-release product (Ditropan XL®) now includes a statement that safety and effectiveness has been established in children as young as 6 years of age.

Temozolomide (Temodar®; Schering) is currently approved by the FDA for the treatment of adults with refractory anaplastic astrocytoma. The results of two pediatric studies, one with 63 glioma and astrocytoma patients and a second with 122 patients who had a variety of CNS and non-CNS tumors, were submitted to the FDA in 2002. Based on these data, however, it was determined that effectiveness in children had not been demonstrated. The adverse effect profile of the drug does appear to be similar in children and adults.

Largely as a result of the Pediatric Exclusivity Program, a total of 15 drug products underwent labeling changes during the last year to incorporate pediatric information. As hoped, the program has become a useful catalyst for manufacturers to conduct pediatric safety and efficacy studies. For more information, the FDA Center for Drug Evaluation and Research website[1] contains a summary of the labeling changes with direct links to the newly revised product labeling.

Contributing Editor: Marcia L. Buck, Pharm.D.
Editorial Board: Anne E. Hendrick, Pharm.D. Michelle W. McCarthy, Pharm.D. Kristi N. Hofer, Pharm.D.

If you have comments or suggestions for future issues, please contact us at Box 800674, UVA Health System, Charlottesville, VA 22908 or by e-mail to This newsletter is also available at


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