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 june
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:
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.
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.
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.
Peter R. Starke, M.D.
Joyce Weaver, Pharm.D.
Badrul A. Chowdhury, M.D., Ph.D.
Food and Drug Administration
Rockville, MD 20857
Hickson GB, Altemeier WA, Clayton EW. Should promethazine
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).
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]. "
    [Show abstract] [Hide abstract] ABSTRACT: Cough syrups are widely used in the developing world, but safety of their use in infants and children less than two years has not been well documented. Some syrups contain multiple combinations of such drugs as promethazine, diphenhydramine and ephedrine; which are individually now contraindicated in children less than two years. Despite this, the syrups are available as over the counter drugs and may be dispensed to mothers who are unaware of the potentially hazardous effects to their infants. A descriptive cross-sectional study was used to investigate suitability of cough syrups sold within Eldoret municipality for use in children less than two years of age based on their formulations and available literature.Two semi-structured questionnaires were administered to pharmacy attendants and mothers attending sick child clinic at a referral hospital to establish whether cough syrups containing more than one active ingredient of compounds, now contraindicated in children are administered to infants, and awareness of potential serious adverse effects. Data from labeled contents of cough syrups from retail pharmacies was recorded and corroborated with information from literature to determine those deemed to contain the ingredients. The second questionnaire was administered to mothers with children less than two years to ascertain whether they had used the identified syrups. A total of 260 mothers and 55 pharmacy attendants were interviewed.There was widespread use of the syrups in children, including infants, with 192 (74%) of the respondents having used identified syrups and over 90% of these on children less than 2 years including those less than three months.146 (76%) mothers had administered the syrup at double the recommended dose.The regulatory authorities should make concerted efforts to discourage use of cough syrups containing ingredients that pose adverse events to infants, including campaigns to educate pharmacy workers and mothers.
    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. "
    [Show abstract] [Hide abstract] ABSTRACT: This article reviews the molecular biology of the interaction of histamine with its H1-receptor and describes the concept that H1-antihistamines are not receptor antagonists but are inverse agonists i.e. they produce the opposite effect on the receptor to histamine. It then discourages the use of first-generation H1-antihistamines in clinical practice today for two main reasons. First, they are less effective than second generation H1-antihistamines. Second, they have unwanted side effects, particularly central nervous system and anti-cholinergic effects, and have the potential for causing severe toxic reactions which are not shared by second-generation H1-antihistamines. There are many efficacious and safe second-generation H1-antihistamines on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine and fexofenadine are the most efficacious in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals while fexofenadine has a relatively short duration of action requiring twice daily administration for full all round daily protection. While desloratadine is less efficacious, it has the advantages of rarely causing somnolence and having a long duration of action. Lastly, all H1-antihistamines have anti-inflammatory effects but it requires regular daily dosing rather than dosing ‘on-demand’ for this effect to be clinically demonstrable.
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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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