n engl j med 352;25 www.nejm.orgjune 23, 2005
cannot be overemphasized. The schema of tympan-
ic-membrane evaluation was offered as a tool for a
limited subgroup of persons involved in mass-cas-
ualty situations who have been spared fragment in-
juries but might have sustained a blast injury. We
agree that patients who incur pulmonary injuries
from a blast, particularly in a confined space, will
have immediate symptoms.
Ralph G. DePalma, M.D.
Veterans Health Administration
Washington, DC 20420
David G. Burris, M.S.
Howard R. Champion, F.R.C.S.
Uniformed Services University of the Health Sciences
Bethesda, MD 20814
Boxed Warning Added to Promethazine
Labeling for Pediatric Use
to the editor:
was added to the labeling for promethazine hydro-
chloride (Phenergan), including a contraindication
for use in children less than two years of age and a
strengthened warning with regard to use in chil-
dren two years of age or older. We describe the basis
for this action.
Promethazine is widely used in children as an an-
tihistamine, antiemetic, and sedative. Since its ap-
proval 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.
these adverse events, particularly respiratory de-
pression 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 anes-
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
In late 2004, a “boxed warning”
The occurrence 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 neurolep-
tic 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 de-
pression. Serious outcomes, including death, dis-
ability, life-threatening events, and hospitalization,
occurred with all routes of administration (oral, rec-
tal, and parenteral).
We determined that the unpredictable nature of
the adverse events and their serious outcomes jus-
tified further strengthening of warnings and con-
traindications and the addition of a boxed warning
for the use of promethazine in children.
Peter R. Starke, M.D.
Joyce Weaver, Pharm.D.
Badrul A. Chowdhury, M.D., Ph.D.
Food and Drug Administration
Rockville, MD 20857
in liquid form be available without prescription? Pediatrics 1990;86:
Cote CJ, Karl HW, Notterman DA, Weinberg JA, McCloskey C.
Adverse sedation events in pediatrics: analysis of medications used
for sedation. Pediatrics 2000;106:633-44.
American Academy of Pediatrics Committee on Drugs. Reap-
praisal of lytic cocktail/demerol, phenergan, and thorazine (DPT)
for the sedation of children. Pediatrics 1995;95:598-602.
Specific requirements on content and format of labeling for hu-
man prescription drugs, 21 C.F.R. § 201.57 (2001).
Hickson GB, Altemeier WA, Clayton EW. Should promethazine
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