Correspondence

An Unusual Outbreak of Hypoglycemia

N Engl J Med 2009; 360:734-736February 12, 2009

Article

To the Editor:

The off-label use of drugs for the enhancement of sexual performance in persons without erectile dysfunction is a phenomenon that is increasingly recognized.1 These drugs are available in illegal forms, including counterfeit versions of brand-name drugs for the treatment of erectile dysfunction and purported herbal remedies containing synthetic phosphodiesterase type 5 inhibitors.2 We describe an outbreak of severe hypoglycemia in Singapore; this outbreak was associated with contamination of illegal sexual-enhancement drugs with glyburide.

Between January 1 and May 26, 2008, a total of 150 nondiabetic patients with severe hypoglycemia were admitted to the five public hospitals in Singapore. All the patients except one were men, and they ranged in age from 19 to 97 years (median, 51). Seven patients remained comatose as a result of prolonged neuroglycopenia, and four subsequently died.

Glyburide was detected in blood or urine samples obtained from 127 of these patients (85%). On specific questioning, 45 patients (30%) admitted ingesting illegal sexual-enhancement drugs before the onset of hypoglycemia. Drug samples obtained from these patients and from drugs seized in police raids were analyzed by means of high-performance liquid chromatography. Four preparations were contaminated with glyburide in amounts ranging from 13 to 100 mg per tablet (Figure 1AFigure 1Contamination of Sexual-Enhancement Drugs.). These drugs included a counterfeit of Cialis (tadalafil) and three herbal preparations for the purported treatment of erectile dysfunction (Power 1 Walnut, Santi Bovine Penis Erecting Capsule, and Zhong Hua Niu Bian).3 All four products also contained sildenafil in amounts ranging from 0.5 to 110.0 mg per tablet. Santi Bovine Penis Erecting Capsule and Zhong Hua Niu Bian also contained trace amounts of tadalafil and sibutramine.

Batches of Power 1 Walnut and Santi Bovine material manufactured before January 2008 were tested and contained only sildenafil, suggesting that the contamination was recent (Figure 1B). Between January and June 2008, similar cases of hypoglycemia were reported in the press in Hong Kong; these reports implicated other brands of illegal sexual-enhancement drugs.4,5 We speculate that simultaneous contamination of several brands of drugs is consistent with a common manufacturing source. The drug packaging contained names of fictitious overseas factories, so it is not known whether there was deliberate or accidental contamination.

It would appear that more effective collaboration between national and international drug-regulatory bodies and enforcement agencies will be required to address clandestine manufacturing processes, the cross-border movement of drugs, and the subsequent spread of these adulterated medications through online sources.

We believe that physicians should be cognizant of this phenomenon when evaluating patients with severe unexplained hypoglycemia, particularly if a clustering of cases is noted. Furthermore, consumers should be informed of the risks associated with these illegally produced drugs.

Shih Ling Kao, M.B., B.S., M.R.C.P.
National University Hospital, Singapore 119074, Singapore

Cheng Leng Chan, B.Sc. (Pharm.), B.Sc. (Pharm.)
Belinda Tan, B.Sc. (Pharm.), B.Sc. (Pharm.)
Health Sciences Authority, Singapore 138667, Singapore

C.C. Tchoyoson Lim, F.R.C.R., M.Med.
National Neuroscience Institute, Singapore 308433, Singapore

Rinkoo Dalan, M.R.C.P.
Tan Tock Seng Hospital, Singapore 308433, Singapore

Daphne Gardner, M.B., B.S., M.R.C.P.
Singapore General Hospital, Singapore 169608, Singapore

Edward Pratt, B.Sc., M.R.C.P.
Changi General Hospital, Singapore 529889, Singapore

Marilyn Lee, M.B., B.S., M.R.C.P.
Alexandra Hospital, Singapore 159964, Singapore

Kok Onn Lee, M.D.
National University Hospital, Singapore 119074, Singapore

We thank Min Yong Low, Health Sciences Authority, Singapore, for the chromatograms.

5 References

1. 1

   Beyond therapy: biotechnology and the pursuit of happiness. Washington, DC: The President's Council on Bioethics, 2003:104.
   

2. 2

   Poon WT, Lam YH, Lai CK, Chan AY, Mak TW. Analogues of erectile dysfunction drugs: an under-recognised threat. Hong Kong Med J 2007;13:359-363
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3. 3

   HSA alerts on wider spread of harmful illegal health products. Singapore: Health Sciences Authority, April 11, 2008 (press release). (Accessed January 23, 2009, at http://www.hsa.gov.sg/publish/hsaportal/en/news_events/press_releases/2008.html.)
   

4. 4

   Public urged not to consume capsules for treating sexual dysfunction with undeclared drug. Hong Kong: Department of Health, February 5, 2008 (press release). (Accessed January 23, 2009, at http://www.dh.gov.hk/textonly/english/press/2008/080205-2.html.)
   

5. 5

   Public urged not to consume products for managing sexual dysfunction with undeclared drug ingredients. Hong Kong: Department of Health, June 4, 2008 (press release). (Accessed January 23, 2009, at http://www.dh.gov.hk/textonly/english/press/2008/080604-2.html.)
   

Citing Articles (12)

Citing Articles

1. 1

   G. Jackson, S. Patel, S. Khan. (2011) Assessing the problem of counterfeit medications in the United Kingdom. International Journal of Clinical Practiceno-no
   CrossRef

2. 2

   Susan D Myers, Marla B Royne, George D Deitz. (2011) Direct-to-Consumer Advertising: Exposure, Behavior, and Policy Implications. Journal of Public Policy & Marketing 30:1, 110-118
   CrossRef

3. 3

   Wayne J.G. Hellstrom. (2011) The Growing Concerns Regarding Counterfeit Medications. The Journal of Sexual Medicine 8:1, 1-3
   CrossRef

4. 4

   J. Dean, R. Klep, J. W. Aquilina. (2010) Counterfeit dapoxetine sold on the Internet contains undisclosed sildenafil. International Journal of Clinical Practice 64:9, 1319-1322
   CrossRef

5. 5

   Minoru Sugita, Michiko Miyakawa. (2010) Economic analysis of use of counterfeit drugs: health impairment risk of counterfeit phosphodiesterase type 5 inhibitor taken as an example. Environmental Health and Preventive Medicine 15:4, 244-251
   CrossRef

6. 6

   Chris G. McMahon. (2010) Get a Better Erection!-Hope for Sale-Use Sexual Snake Oil. Journal of Sexual Medicine 7:5, 1699-1702
   CrossRef

7. 7

   Gabriel Schnetzler, Ian Banks, Mike Kirby, Kelly H. Zou, Tara Symonds. (2010) Characteristics, Behaviors, and Attitudes of Men Bypassing the Healthcare System When Obtaining Phosphodiesterase Type 5 Inhibitors. Journal of Sexual Medicine 7:3, 1237-1246
   CrossRef

8. 8

   G. Jackson, S. Arver, I. Banks, V. J. Stecher. (2010) Counterfeit phosphodiesterase type 5 inhibitors pose significant safety risks. International Journal of Clinical Practice 64:4, 497-504
   CrossRef

9. 9

   Min-Yong Low, Yun Zeng, Lin Li, Xiao-Wei Ge, Ruth Lee, Bosco-Chen Bloodworth, Hwee-Ling Koh. (2009) Safety and Quality Assessment of 175 Illegal Sexual Enhancement Products Seized in Red-Light Districts in Singapore. Drug Safety 32:12, 1141-1146
   CrossRef

10. 10

    Thomas Y. K. Chan. (2009) Outbreaks of severe hypoglycaemia due to illegal sexual enhancement products containing undeclared glibenclamide. Pharmacoepidemiology and Drug Safety 18:12, 1250-1251
    CrossRef

11. 11

    G. R. Ling, K. Singh, S. Y. Wong, V. K. L. Toh. (2009) Severe neuroglycopaenia secondary to severe hypoglycaemia from serendipitous overdose of gliclazide without adrenergic or autonomic response. Diabetic Medicine 26:11, 1182-1183
    CrossRef

12. 12

    Kao, Shih Ling, , (Pharm.), Cheng Leng Chan, B.Sc., (Pharm.), Belinda Tan, B.Sc., , Lim, C.C. Tchoyoson, , Dalan, Rinkoo, , Gardner, Daphne, , Pratt, Edward, , Lee, Marilyn, , Lee, Kok Onn, . (2009) An Unusual Outbreak of Hypoglycemia — A Correction. New England Journal of Medicine 360:23, 2482-2483
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