Boxed Warning Added to Promethazine Labeling for Pediatric Use

Article (PDF Available)inNew England Journal of Medicine 352(25):2653 · July 2005with14 Reads
DOI: 10.1056/NEJM200506233522522 · Source: PubMed
n engl j med
352;25
www.nejm.org june
23, 2005
correspondence
2653
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
rgdepalma@mail.va.gov
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:
In late 2004, a “boxed warning”
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.
1,2
The occurrence of
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-
thetic 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 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.
4
Peter 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:
221-5.
2.
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.
3.
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.
4.
Specific requirements on content and format of labeling for hu-
man prescription drugs, 21 C.F.R. § 201.57 (2001).
The New England Journal of Medicine
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    • "Other adverse effects include cardiac arrests and neuroleptic malignant syndrome [16]. This led to withdrawal of its use in children less than 2 years in America in 2004, and strengthened warning (boxed warning) in children over 2 years [12,13,171819 . Promethazine is therefore not recommended to be used in children less than 2 years, and this warning is contained in the manufacturers manual [20]. "
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    Full-text · Article · Nov 2015
    • "In the United States, reports of serious and often life-threatening adverse events of promethazine in children led to a "boxed warning" being added in 2004 to the labeling of promethazine. The warning included a contraindication for use in children younger than 2 years and a strengthened warning with regard to use in children 2 years of age or older[24]. In February 2009, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom[25] advised that cough and cold remedies containing certain ingredients, including first-generation H1-antihistamines, should no longer be used in children younger than 6 years because the balance of benefit and risks has not been shown to be favorable. "
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    • "n infants, particularly premature neonates, not be able to metabolize promethazine as well as older children and adults due to lower levels of CYP2D6 activity or reduced sulfur stores. FDA (2000) strengthened the warning section of the prescribing information for promethazine to state that it should not be used in children less than 2 years of age. Starke et al. (2005) reported the 22 cases of respiratory depression the FDA between 1969 and 2003 including 7 deaths. As a result, the FDA added a black box warning to promethazine in November 2004, declaring its use in children less than 2 years as contraindicated."
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    TariqTariqM.MM.MM. A. BajwaM. A. Bajwa+5 more authors ...Y. JavedY. Javed
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