DIETHYLENE GLYCOL, PHARMACEUTICAL AGENTS, CHILDREN - NIGERIA
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A ProMED-mail post
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Date: 11 Dec 2009
Source: MMWR (Morbidity and Mortality Weekly Report) [edited]
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http://www.cdc.gov/mmwr/preview/mmwrhtm ... mm5848a2_e>
Fatal Poisoning Among Young Children from Diethylene
Glycol-Contaminated Acetaminophen --- Nigeria, 2008--2009
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On 18 Nov 2008, the Nigerian Federal Ministry of Health (FMOH)
received a report of 13 cases of unexplained acute renal failure
among children from a hospital in Lagos state. Several of the
patients had been exposed to a liquid acetaminophen-based teething
medication. On 21 Nov 2008, officials from the Nigerian National
Agency for Food and Drug Administration and Control (NAFDAC)
discovered diethylene glycol (DEG) in 4 batches of the teething
medication manufactured during August--October 2009. DEG is a toxic
alcohol used in brake fluid, paint, and household cleaning products,
and has been used illegally as a cheap substitute solvent in drug
manufacturing. Previous DEG poisonings resulting from contamination
of medications have been reported in the United States, Nigeria
(1990), Panama, and other countries (1--3), and acute renal failure
(ARF) is a known manifestation of DEG poisoning.
An investigation was launched by the Nigeria Field Epidemiology and
Laboratory Training Program (N-FELTP), CDC, and the Food and Drug
Administration (FDA). This report summarizes the results of the
investigation, which identified 57 cases of DEG poisoning among
children aged =3 years during August 2008--January 2009, of whom 54
died. Of the 57 children with DEG poisoning, 96 percent had exposure
to the acetaminophen-based teething medication (My Pikin). DEG
contamination was identified in 6 bottles of the medication from
patient households and 4 batches from the facility in which the
medication was manufactured. Well-developed and strictly enforced
pharmaceutical quality control measures and training programs can
prevent DEG-associated large-scale poisoning events (4,5).
The initial 13 cases of ARF reported to FMOH occurred over a period
of 2 weeks, and represented a large increase over the baseline
incidence of ARF at the hospital of 1--2 cases per month. All the
cases had occurred in children aged less than or equal to 3 years.
Hospitals in Kaduna and Osun states reported similar clusters of ARF.
Because several of the ill patients had been exposed to the
acetaminophen-based teething medication before disease onset, the
medication became the focus of the initial investigation. On 21 Nov
2008, after NAFDAC officials discovered DEG contamination in batches
of the medication, a full product recall was initiated, and the
manufacturing facility was shut down. FMOH requested assistance from
CDC for the epidemiologic investigation, and NAFDAC asked FDA to
inspect the facility that had manufactured the teething medication.
CDC and FDA investigators arrived in mid-January [2009], after the
product recall had been issued, and after the outbreak had peaked.
To ascertain cases and determine the scope of the poisoning, N-FELTP
and FMOH conducted active, hospital-based surveillance in the 3
states (Kaduna, Lagos, and Osun) to identify physician-diagnosed ARF
cases of any etiology in children aged less than 18 years. No
additional cases were detected from FMOH nationwide passive
surveillance. By 8 Jan 2009, 111 physician-diagnosed ARF cases of any
etiology had been identified, and 4 additional cases were identified
by field investigators through hospital-based surveillance in the 3
states, for a total of 115 ARF cases.
To differentiate background cases of ARF (of any etiology) from ARF
cases associated with DEG poisoning, investigators focused further
investigations on ARF cases that were unexplained. A confirmed case
of unexplained ARF was defined as acute-onset anuria or oliguria of
unknown etiology lasting =24 hours, with onset after 1 Aug 2008 (the
manufacturing date of the 1st known DEG-contaminated batch). Cases
were classified solely on the clinical observation of urine output,
and no laboratory confirmation of ARF was available. N-FELTP or CDC
investigators used a standard questionnaire to interview 71 parents,
guardians, or physicians of the 115 ARF patients; the remaining 44
families could not be contacted or located. Information collected
included illness characteristics, underlying health conditions,
medical evaluation, and medication exposures. During interviews,
residual medications in households were collected and sent to FDA's
Forensic Chemistry Center for analysis by gas chromatography--mass
spectrometry for DEG.
Based on 71 completed interviews, 57 (80 percent) patients met the
confirmed case definition for unexplained ARF. Of these, 37 (65
percent) patients were male, and 56 (98 percent) were previously
healthy (one patient had sickle cell disease). Median patient age was
12 months (range: 1 week--27 months). Of the 57 patients, 55 (96
percent) had exposure to the teething medication, and 16 (28 percent)
had received the medication after the product recall in Nigeria was
announced. A total of 54 patients (95 percent) died.
Of 46 (81 percent) patients with available information, the median
time from exposure to ARF onset was 5.6 days (range: 0--24 days).*
For 52 of the patients with information available, the mean interval
between ARF onset and death was 6.8 days (range: 1--19 days). No
biologic samples from patients could be obtained because of the high
fatality rate and retrospective nature of the investigation. Among
the 57 patients, 24 (42 percent) underwent dialysis and 2 (4 percent)
received fomepizole, an antidote for ethylene glycol toxicity. No
particular treatment combination appeared to improve survival.
During the interviews, 34 medication bottles from 13 different
patients were collected, including 7 bottles of the teething
medication. DEG contamination (17 percent--21 percent DEG by
weight)** was identified in 6 of those bottles. Laboratory analyses
identified a 2nd contaminated medication (0.5 percent DEG) in another
acetaminophen-based syrup by a different manufacturer. One patient
had exposure to both medications. The remaining 26 medications tested
negative for DEG contamination. Although the exact mechanism of
contamination was not identified, facility inspection revealed
multiple errors common to previous DEG-associated large-scale
poisoning events (6), including 1) use of unknown or unapproved raw
material suppliers for propylene glycol, 2) lack of certificates of
analysis from suppliers to certify the ingredient's identity and
purity, 3) failure to perform propylene glycol identity testing, 4)
failure to analyze finished product for DEG, and 5) failure to track the !
distribution of finished product. The product recall resulted in the
confiscation of 7616 bottles of the teething medication, representing
51 percent of approximately 15 000 contaminated bottles produced
during August--October 2008. Investigators convened key stakeholders
within FMOH and from national and international agencies in February
[2009] to produce additional press releases for radio, television,
and print media to support the product recall. In addition,
investigators recommended further investigation of the 2nd brand of syrup.
[Reported by: A Abubukar, E Awosanya, O Badaru, S Haladu, P Nguku,
Nigerian Field Epidemiology and Laboratory Training Program. P
Edwards, R Noe, M Teran-Maciver, A Wolkin, L Lewis, National Center
for Environmental Health; M Nguyen, EIS Officer, CDC.]
MMWR Editorial Note:
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This report describes Nigeria's 2nd and largest DEG-associated
large-scale poisoning since 1990. The hallmark of DEG poisoning is
ARF. The temporal association between ARF and reported exposure to
the implicated medication among 96 percent of the children in this
event, combined with discovery of DEG contamination in samples of the
implicated medication from patients' homes, indicate that the
medication was the poisoning source. A substantial proportion of the
children with DEG poisoning (28 percent) were given the implicated
teething medication after the product recall was announced, even
though the recall targeted pharmacies and consumers. Product recalls
will never completely eliminate the risk for harmful exposure after a
product is distributed widely. Safety measures must be directed
primarily at preventing contamination during manufacture and before
sale of the product.
During the past 70 years, at least 12 occurrences of DEG
contamination in oral and topical medications have resulted in at
least 450 deaths (1--3). These large-scale poisonings have occurred
predominantly in developing countries and have been associated with
inadequate adherence to safe manufacturing practices, lack of
enforcement of safe practices, or what appear to be intentionally
deceptive drug manufacturing practices (7). In all but one of the 12
DEG mass-poisoning events (7), propylene glycol or glycerin was the
intended diluent. Because these diluents have very different
manufacturing methods and neither produces DEG as a byproduct, simple
errors of cross-contamination during manufacturing cannot account for
the frequent substitution of DEG in pharmaceuticals. Economically
motivated substitution was suspected in several prior outbreaks,
because DEG is less expensive than pharmaceutical-grade solvents.
Use of safe manufacturing practices might have prevented this event.
Simple, rapid, and low-cost assays using thin-layer chromatography
(TLC) have been developed to detect and quantify DEG contamination
(8). Direct visual inspection of TLC sheets can detect gross
contamination at levels of 2 percent DEG in acetaminophen elixirs and
6 percent DEG in glycerin. The assay costs USD 1.00 or less per test,
can be performed without laboratory facilities, and takes
approximately 20 minutes. Although detection limits of 0.1 percent
using TLC methods require more sophisticated equipment, these
low-cost methods would have detected contamination and likely
prevented many of the fatalities in this event.
Because DEG poisonings continue to occur, in 2000 the World Health
Organization (WHO) introduced the 1st global training program for
industry personnel on safe manufacturing practices.*** In 2006, the
International Medical Products Anti-Counterfeiting Taskforce was
launched to strengthen regulatory enforcement and communication
within and among countries.**** In 2008, a new monograph on the safe
manufacturing of oral liquid preparations was added to The
International Pharmacopoeia, in response to several DEG poisoning
events involving liquid medications.** Globalization of
pharmaceutical manufacturing and distribution has heightened the need
for more uniform regulation and international cooperation. These
measures address specific vulnerabilities in the production,
inspection, and distribution of pharmaceuticals internationally.
Countries that inadequately implement safe manufacturing standards,
poorly enforce quality controls, or lack adequate training programs
remain at risk!
for medication-associated poisonings.
Acknowledgment
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The findings in this report are based, in part, on contributions by J
Schier, National Center for Environmental Health, CDC.
References
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1. Geiling EMK, Cannon PR. Pathologic effects of elixir of
sulfanilamide (diethylene glycol) poisoning: a clinical and
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2. Okuonghae HO, Ighogboja IS, Lawson JO, Nwana EJ. Diethylene glycol
poisoning in Nigerian children. Ann Trop Paediatr 1992;12:235--8.
3. Rentz ED, Lewis L, Mujica OJ, et al. Outbreak of acute renal
failure in Panama in 2006: a case-control study. Bull World Health
Organ 2008;86:749--56.
4. World Health Organization. Counterfeit drugs kill! IMPACT --
International Medical Products Anti-Counterfeiting Task Force.
Geneva, Switzerland: World Health Organization; 2008. Available at
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http://www.who.int/impact/en/>. Accessed 4 Dec 2009.
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<
http://www.fda.gov/downloads/safety/saf ... 184049.pdf>.
Accessed 4 Dec 2009.
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Drug Evaluation and Research; 2007. Available at
<
http://www.fda.gov/downloads/drugs/guid ... 070347.pdf>.
Accessed 1 Dec 2009.
7. Schier J, Rubin C, Miller D, Barr D, McGeehin M.
Medication-associated diethylene glycol mass poisoning: a review and
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8. Kenyon AS, Xiaoye S, Yan W, Har NW. Simple, at-site detection of
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* One parent estimated the onset of oliguria or anuria occurred 1 day
before exposure to the medication, which might reflect the difficulty
of recalling precise use of over-the-counter medications.
** DEG is a clear, colorless, odorless, mildly sweet liquid, and an
efficient solvent for water-insoluble active ingredients in
medications. DEG is readily absorbed orally and transdermally.
Although a safe level has not been established in humans, a safety
limit of 0.1 percent DEG for screening substances used to manufacture
pharmaceutical products (e.g., active ingredients and excipients),
was set by the United States Pharmacopeia, the official standards
authority for health products sold in the United States. Data from
prior outbreaks suggest that the minimum toxic dose is less than 1
mL/kg. Although the mechanism for toxicity is still unclear,
2-hydroxyethoxyacetic acid, the metabolic product of the enzyme
aldehyde dehydrogenase, is considered to be a renal toxin.
*** Additional information available at
<
http://www.who.int/medicines/areas/qual ... index.html>
**** Additional information available at <
http://www.who.int/impact/en>.
