Correspondence
Boxed Warning Added to Promethazine Labeling for Pediatric Use
N Engl J Med 2005; 352:2653June 23, 2005
- Article
To the Editor:
In late 2004, a “boxed warning” was added to the labeling for promethazine hydrochloride (Phenergan), including a contraindication for use in children less than two years of age and a strengthened warning with regard to use in children two years of age or older. We describe the basis for this action.
Promethazine is widely used in children as an antihistamine, antiemetic, and sedative. Since its approval in 1951, serious and often life-threatening adverse events, including respiratory depression, oversedation, agitation, hallucinations, seizures, and dystonic reactions, have been reported with promethazine use in children.1,2 The occurrence of these adverse events, particularly respiratory depression reported when promethazine was used in combination with other drugs that themselves may cause respiratory depression, led the American Academy of Pediatrics in 1995 to reappraise the use of promethazine in combination with other drugs and to discourage the use of promethazine as anesthetic premedication.3
In 2000, the warnings section of the label was strengthened to recommend that promethazine not be used in children younger than two years of age and that it be used with caution in children two years of age or older because of the potential for fatal respiratory depression. Despite these labeling changes, the Food and Drug Administration (FDA) continued to receive reports of life-threatening and fatal respiratory depression in young children. In 2004, we reviewed all cases of serious adverse events reported to the FDA that involved children (age range, birth to 16 years) who had received any formulation of promethazine. Reports on adverse events in 125 patients were submitted between 1969 and 2003. The adverse events included 38 cases of respiratory depression, apnea, or cardiac arrest; 29 cases of extrapyramidal dystonic reactions; 24 cases of other central nervous system reactions; 15 cases of seizures or seizure-like activity; 12 cases of dermatologic reactions, and 5 cases of the neuroleptic malignant syndrome. These reports to the FDA included respiratory depression in 22 patients who were 1.5 months to 2 years of age, 7 of whom died. Nine of these 22 patients received 1 mg or less of promethazine per kilogram of body weight, plus another drug with respiratory depressant effects. A wide range of weight-based doses (0.45 to 6.4 mg per kilogram) was associated with respiratory depression. Serious outcomes, including death, disability, life-threatening events, and hospitalization, occurred with all routes of administration (oral, rectal, and parenteral).
We determined that the unpredictable nature of the adverse events and their serious outcomes justified further strengthening of warnings and contraindications and the addition of a boxed warning for the use of promethazine in children.4
4 ReferencesPeter R. Starke, M.D.
Joyce Weaver, Pharm.D.
Badrul A. Chowdhury, M.D., Ph.D.
Food and Drug Administration, Rockville, MD 20857
starkep@cder.fda. gov 1
Hickson GB ,Altemeier WA ,Clayton EW . Should promethazine in liquid form be available without prescription? Pediatrics 1990;86:221-225
Web of Science | Medline2
Cote CJ ,Karl HW ,Notterman DA ,Weinberg JA ,McCloskey C . Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics 2000;106:633-644
CrossRef | Web of Science | Medline3
American Academy of Pediatrics Committee on Drugs
Web of Science | Medline4
Specific requirements on content and format of labeling for human prescription drugs, 21 C.F.R. § 201.57 (2001).
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