Recent Actions by the Food and Drug Administration

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2005;11(3) 

In This Article

Labeling Changes Under the Pediatric Exclusivity Act

In the past year, the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) has made a number of significant changes in the labeling of prescription drugs for children as part of the Pediatric Exclusivity Program.[1] A number of agents received pediatric indications. In several other cases, preliminary studies failed to demonstrate safety and efficacy in children, but provided useful information on dosing, pharmacokinetics, or adverse effects that might aid prescribers in determining the appropriateness of these agents in children. In addition to these changes, there have been several important FDA Safety Alerts involving medications commonly used in children.[2,3,4]

The product labeling for anagrelide (Agrylin®; Shire) was changed in December 2004 to include information on the pharmacokinetics, dosing, and adverse effects in children 6 to 17 years of age. Anagrelide is used in the treatment of thrombocytopenia due to myeloproliferative disorders.

Labeling for benazepril (Lotensin®; Novartis), an angiotensin converting enzyme inhibitor, was changed in March 2004 to include an indication for children 6 to 16 years of age. Benazepril is not recommended for children under 6 years of age (because of lack of sufficient data) or in patients with renal dysfunction. Pharmacokinetic studies have shown a significantly higher clearance rate in children than in adults, with an elimination half-life 1/3 of adult values. Instructions for the preparation of an oral suspension have also been included.

Ciprofloxacin (Cipro®; Bayer), a quinolone antibiotic, has been approved for use in children 1 to 17 years of age for the treatment of complicated urinary tract infections and pyelonephritis. The drug is not recommended as first-line therapy in this age range. In clinical trials, there was an increased risk of adverse effects in the patients receiving ciprofloxacin compared to those given placebo, including adverse effects related to joints and surrounding tissues. The most frequent adverse effects in children were gastrointestinal (15% compared to 9% of controls) and musculoskeletal (9.3% compared to 6% of controls).

During the past year, only one agent received simultaneous pediatric and adult approval with an original New Drug Application. Clofarabine (Clolar®; Genzyme) is indicated for the treatment of relapsed or refractory acute lymphoblastic leukemia after at least two prior regimens. This agent is currently approved for use in patients 1 to 21 years of age.

The product information for desloratadine (Clarinex®; Schering) was amended in September 2004 to include an indication for patients 2 years of age and greater with perennial allergic rhinitis and chronic idiopathic urticaria. Information on dosing, pharmacokinetics, and adverse effects has been included in the product labeling.

The labeling of dorzolamide (Trusopt®; Merck) was modified in April 2004 to include efficacy and safety data in children. Dorzolamide reduces intraocular pressure by decreasing production of aqueous humor in patients with glaucoma or ocular hypertension.

The use of fenoldopam (Corlopam®; Hospira) was approved for the short-term reduction of elevated blood pressure in hospitalized pediatric patients greater than one month of age or weighing greater than 2 kg. Dosing, pharmacokinetic, and adverse effect information is now available in the product labeling.

In a clinical trial, the combination of glyburide and metformin (Glucovance®; BMS) was not found to be statistically superior to either agent given alone for pediatric patients with type 2 diabetes mellitus.

New information has been added to the product labeling for irinotecan. Clinical trials did not establish the effectiveness of irinotecan (Camptosar®; Pfizer) in children. A phase 2 trial which enrolled 21 children with previously untreated rhabdomyosarcoma was halted because of a 23.6% incidence of progressive disease and 14% incidence of early deaths. Adverse effect data from a phase 2 trial of irinotecan in 170 children with refractory solid tumors was similar to that previously reported in adults, with neutropenia in 31.8% of patients and diarrhea in 20.6% of patients. In another study, dehydration occurred in 28.6% of the patients. Several experienced severe hypokalemia and hyponatremia. Serious infections were reported in 23.8% of patients.

In June 2004, lansoprazole (Prevacid®; Tap) labeling was amended to include an indication for patients 12 to 17 years of age. This drug, a proton pump inhibitor used to decrease gastric acid production, was previously approved for patients 1 to 11 years of age and adults.

The safety and efficacy of leflunomide (Arava®; Aventis) has not been fully evaluated in children with juvenile rheumatoid arthritis (JRA), but preliminary information was added to the product labeling in March 2004. In a double-blind study of 94 children with JRA, 68% of those given leflunomide demonstrated clinical improvement, compared to 89% of patients on standard therapies. In a study of 74 children with JRA, adverse effects were similar to those reported in adults. Fourteen patients experienced elevated liver function tests, with 5 patients having values greater than three-fold the upper limit of normal.

The angiotensin receptor blocker losartan (Cozaar®; Merck) now has labeling for use in hypertensive patients between 6 and 16 years of age. Information on dosing, pharmacokinetics, and adverse effects has been included, as well as information on the preparation of an extemporaneous oral suspension. Lorsartan is currently not recommended for patients less than 6 years of age or in patients with renal dysfunction.

The labeling of once-daily methylphenidate (Concerta®; Alza) has been expanded to include a new strength and information on the dosing, pharmacokinetics, and adverse effects in children 13 to 17 years of age. A higher maximum dose for adolescents has also been incorporated.

Because the data submitted to the FDA were deemed inadequate to determine whether chronic use of stimulants suppresses growth, the labeling of this product has been amended to highlight the need for monitoring growth during treatment. Patients who are not growing or gaining weight should have their treatment interrupted. In addition, caution should be used when prescribing methylphenidate for patients with hypothyroidism, hypertension, or cardiovascular conditions that might be worsened by drug-related elevations in blood pressure or heart rate.

A protease inhibitor for the treatment of patients with HIV-1 infection, nelfinavir (Viracept®; Pfizer), has been approved for use in children 2 to 13 years of age. New dosing information has been added to the labeling for this population. In addition, the results of pharmacokinetic studies in patients from birth to 13 years of age have been added, with attention to the problem of highly variable drug exposure in children.

The labeling of nizatidine (Axid®; Reliant Pharma), a histamine (H2) blocker, was changed in May 2004 to include an indication for patients 12 years of age and older. Dosing, pharmacokinetic, and safety data were added.

The safety and efficacy of paricalcitol (Zemplar®; Abbott) was studied in a 12-week trial in 29 children with end-stage renal disease. Nine of the 15 patients (60%) given paricalcitol had significant decreases from baseline parathyroid hormone levels compared to 3 of 14 patients (21%) in the placebo group.

Remifentanil (Ultiva®; Abbott) labeling was amended in March 2004 to include information on its use for maintenance of anesthesia in infants. Because of the highly variable clearance rate observed during clinical trials in neonates, a recommendation for careful dose titration has been included.

Labeling for sodium ferric gluconate complex (Ferrlecit®; Watson) was amended in August 2004 to include patients 6 to 15 years of age. Information on dosing, pharmacokinetics, and adverse effects in this age group has been added.

Five clinical trials of sumatriptan (Imitrex Nasal Spray®; Glaxo) have failed to show significant benefit when compared to placebo in pediatric patients with migraines. Information from these trials, including the adverse effects observed in children, was added to the product labeling. At this time, the use of sumatriptan in patients less than 18 years of age is not recommended.

Pharmacokinetic data in patients 11 to 15 years of age was added to the product information for tolterodine (Detrol LA®; Pfizer). This drug is an anticholinergic used for patients with an overactive bladder.

The antidepressant venlafaxine (Effexor® and Effexor XR®; Wyeth) was studied in adolescents with depression, but did not show significant benefit compared to placebo. During placebo-controlled trials, decreased appetite and a reduced growth velocity were observed. Elevations in blood pressure and serum cholesterol were reported in children at rates similar to those observed in adults.

As with sumatriptan, studies with zolmitripan (Zomig®; AstraZeneca) in adolescents with migraines have not established safety and efficacy when compared to placebo. The adverse effects observed were similar to those in adults.


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