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Internet‐Ordered Viagra (Sildenafil Citrate) Is Rarely Genuine
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Internet-Ordered Viagra (Sildenafil Citrate) Is Rarely Genuine
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Neil Campbell,* John P. Clark,* Vera J. Stecher, PhD,* and Irwin Goldstein, MD† *Pfizer Inc, New York, NY, USA; †Alvarado Hospital, San Diego, CA, USA DOI: 10.1111/j.1743-6109.2012.02877.x
ABSTRACT
Introduction. Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). Methods. Pfizer monitored top search results for the query “buy Viagra” on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. Results. No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal “generic Viagra.” Cost per tablet ranged from $3.28–$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. Conclusion. Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. Campbell N, Clark JP, Stecher VJ, and Goldstein I. Internet-ordered Viagra (sildenafil citrate) is rarely genuine. J Sex Med **;**:**–**. Key Words. Counterfeit; Erectile Dysfunction; Internet; Sildenafil Citrate
Introduction
W
orldwide sales of counterfeit medicines were estimated to reach $75 billion in 2010, representing 90% growth in a 5-year period [1,2]. If past trends continue, worldwide counterfeit drug sales will increase by 25% annually [3]. In the United States, 170% more illegal pharmaceutical products were seized by the Homeland Security Department in 2010 ($5.6 million) [4] than in 2005 ($2.1 million) [5]. Although no type of pharmaceutical is immune from counterfeiting, including cancer medications [6], phosphodiesterase type 5 (PDE5) inhibitor medications have historically been targeted [7–9], likely because of stigma regarding the condition they treat, erectile dysfunction (ED) [9,10]. © 2012 International Society for Sexual Medicine
Internet purchasing has contributed to the explosive growth in counterfeit pharmaceuticals. Little money or expertise is required to create professional-looking Web sites that sell counterfeit drugs to unsuspecting consumers worldwide. A recent study by the National Association of Boards of Pharmacy (NABP) found that the vast majority of Web sites offering prescription-only medications (POMs) for sale are not legitimate [11]. Of 8,353 Internet drug outlets selling POMs, 8,034 (96%) were operating out of compliance with state and federal laws and/or NABP patient safety and pharmacy practice standards, including 6,812 that did not require a valid prescription. Similar results were reported in studies from the United States and Europe examining a variety of POMs [12–15]. J Sex Med **;**:**–**
2 The World Health Organization suggests that medicines purchased over the Internet from sites that conceal their physical address are counterfeit ⱖ50% of the time [16]; in a European study, 62% of medicines ordered via the Internet and without a prescription were substandard or counterfeit [14]. In 2004, European officials assessed that 44% of the PDE5 inhibitor sildenafil citrate (VIAGRA®, Pfizer Inc, New York, NY, USA) sold via the Internet was counterfeit [17]. In a subsequent analysis of samples seized worldwide for suspicion of being counterfeit Viagra, 83% of the samples ordered via the Internet were found to be counterfeit [18]. Last year, one in six Americans purchased prescription medicines via the Internet, meaning that 36 million consumers potentially exposed themselves to counterfeit medicines [19]. Alarmingly, European studies show that the United States is not alone in having a significant portion of the population purchase their pharmaceuticals via the Internet [18,20–22]; perceived cost and time advantages drive this behavior, even though consumers report being aware of potential danger. Recreational users and abusers of PDE5 inhibitor medication also report using the Internet as a source channel [23–25]. Counterfeits are dangerous for multiple reasons. They are not made in accordance with good manufacturing practices, and thus, are free from regulations that guarantee high-quality products [7]. They may contain inactive ingredients that can prevent the appropriate exposure to effective treatment for sometimes fatal conditions [26] or could induce buyers to overmedicate as a way to compensate for lower active drug concentration. They may contain harmful ingredients; an analysis of counterfeit Viagra revealed the presence of contaminants including talcum powder, commercial paint, and printer ink [27]. Counterfeits also may not come with important instructions regarding the use of medication [14]; patients with obvious contraindications to Viagra use have received online prescriptions for the drug [14,28]. Patients who buy counterfeit drugs avoid interaction with the health-care system; in the case of ED, patients deprive themselves of needed screening or treatment for conditions which frequently accompany ED, including diabetes and heart disease [7]. People have died from using counterfeit medications [16], including counterfeit PDE5 inhibitors [29]. This study assessed the requirements for purchase, cost, origin, and content of medications sold J Sex Med **;**:**–**
Campbell et al. via the Internet and purporting to be the PDE5 inhibitor Viagra.
Methods
Procurement Pfizer Global Security monitored top search results for the phrase “buy Viagra” on the leading two Internet search engines from March 14–18, 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Authenticity Evaluation Packaging and tablet attributes of ordered medicines were evaluated by visual and physical methods. Tablets were assessed for chemical composition using Raman and infrared spectroscopic analyses to assess conformance of tablet coating and tablet core formulations to authentic Viagra formulations. Ultraviolet spectroscopic and liquid chromatography/mass spectroscopic analyses were used to assess the content of sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra. All analyses were performed at the Pfizer Intellectual Property Forensic Laboratory in Groton, CT, USA.
Results
Of the 22 Web sites assessed, 100% did not ask for a prescription before purchase as required by law (Table 1); none required a completed health screening to enable purchase. Additionally, 91% of the sites tested claimed to sell medicines identified as “generic Viagra,” which is not approved by the U.S. Food and Drug Administration (FDA). Cost per tablet ranged from $3.28–$33.00. Shipment origins of ordered products were most commonly Hong Kong (N = 11 Web sites), the United States (N = 6), and the United Kingdom (N = 2); others were Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Counterfeit medications were often distinguishable as suspect before tablet analysis. Packaging differed from that of genuine Viagra; blisters occasionally shipped wrapped in magazines or aluminum foil (Figure 1). Blisters were not intact on five samples (19%) assessed (Table 1). Common shortcomings of counterfeit packaging included cited lot
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U.S. Counterfeit Table 1
Analysis of ordering and products received from 22 unique Web sites purporting to sell Viagra
Web site http://www.accessrx.com http://www.onlinepharmacycr.com http://www.atlanticdrugs.com http://www.topills.com http://www.videochron.com http://www.erectiledysfunction-pills.com http://www.directpharma.net http://www.buyingviagra.us http://www.gerryggriffin.com/viagra http://www.v-medical.com/viagra.html http://www.buyviagra4you.com http://www.doctor-approved.org http://www.viagra.gd http://www.viagrabuy.cc http://www.viagra.ac http://fr.pharm4all.com http://de.pharm4all.com http://www.buyviagra1.com http://www.adventuregamingstl.org/ viagra.aspx http://www.buy-viagra-online.me.uk http://www.medical-place.com http://www.buy-viagra.co
Prescription required?
Price per tablet ($)
Postal origin
PI sheet included?
Blister intact on all tablets?
Test result
API (%)
No No No No No No No No No No No No No No No No No No No
29.67 5.95 33.00 12.50 3.28 15.63 11.20 9.06 8.66 12.10 12.90 5.10 9.06 9.15 12.50 21.75 18.50 7.37 12.50
United States United States United States Canada India China Hong Kong Hong Kong Hong Kong United States Hong Kong Hong Kong Hong Kong United States Hong Kong United Kingdom United Kingdom United States Hong Kong
No No No No No No No No No No No No No No No Yes Yes No No
Yes Yes * No Yes Yes No Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes
Authentic Counterfeit Authentic Counterfeit Illegal generic Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Authentic Authentic Counterfeit Counterfeit
N/A 30 N/A 40 N/A 35 35 45 30 30 30 30 40 50 35 N/A N/A 30 40
No No No
10.61 12.50 16.13
Hong Kong Hong Kong Hong Kong
No No No
Yes Yes Yes
Counterfeit Counterfeit Counterfeit
35 35 30
*Not a blister; received as a vial of three loose tablets API = active pharmaceutical ingredient; N/A = not applicable; PI = product information
numbers corresponding to expired products (e.g., 314833021), low-quality printing on the logo side of the foil, a poorly rendered Pfizer logo on the foil side (a non–color-shifting Pfizer logo or inner Pfizer text being foil colored instead of white), and excessively shiny foil on the tablet side of the blister (Figure 2). Shipped medications often lacked the product information leaflet (PIL) required to accompany genuine Viagra (only two shipments [9%] included a genuine PIL; Table 1). Counterfeit tablets generally had similar appearances as genuine Viagra (Figure 3), easily mimicking the blue diamond shape, but often without accurate coloration or logo debossing. A total of 22 sample tablets were analyzed after receipt (Table 1). Seventeen (77%) were counterfeit (Figure 4), four (18%) were authentic, and one (5%) was an illegal generic. Tablet core (Figure 5) and coating (data not shown) formulations did not match those of authentic Viagra. Authentic medications were shipped from the United States and the United Kingdom; the illegal generic shipped from India. The 17 counterfeit samples were analyzed for sildenafil citrate content. API contents varied between 30% and 50% of the label claim (Figure 6). The price per tablet for counterfeits was intermediate to the generic, which was the
cheapest, and authentics, which were the most expensive. Discussion
Unauthorized sales of prescription medication have become rampant, amplified by convenient Internet access and multiple purchasing options. In this study, Internet sites claiming to sell authentic Viagra medication shipped counterfeit medication 77% of the time, and these counterfeits contained only 30% to 50% of the labeled API claim. Our study, which used a prospective assessment of Web sites claiming to sell Viagra, differed from previous studies, which examined the prevalence of counterfeit medications by assessing samples seized by authorities for suspicion of being counterfeit Viagra [18,27]. In seized-sample analyses, some quality of the samples alerted authorities to possible fraud, perhaps contributing to the high percentage of counterfeits encountered. Here, we ordered medications from the most common Web sites returned from popular Internet search engines, meant to simulate the way a patient might research the acquisition of Viagra via the Internet, and still found that an alarmingly high percentage were counterfeit. Caution is warranted when purchasing Viagra through the Internet, even if shipped from within the United States. J Sex Med **;**:**–**
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different medications, including the PDE5 inhibitor Cialis (tadalafil, Lilly USA, Indianapolis, IN, USA), from 13 suspicious Web sites selling POM without a prescription [31]. Testing by the FDA found wide variation in the amount of API present in drugs received, ranging from none to far exceeding labeled doses; regulatory analysis by the drug manufacturer found that they did not meet the company’s U.S. standards [31]. In the U.K. study cited earlier [18], 55 of the 264 Internet-ordered samples were analyzed chemically. Just 16% fell within the regulatory threshold of 5% of labeled sildenafil concentration; 25% contained no sildenafil. Only 2% of samples had API concentration that exceeded the labeled dose of sildenafil. Unfortunately, lowered APIs create the potential that patients could A
B
Figure 1 Counterfeit Viagra packaging. Blisters and blister segment (cutout), as received wrapped in glossy paper (A); loose tablets in plastic wrap (B).
Prevalence and Sildenafil Content of Counterfeit Viagra on the Internet The 77% incidence of counterfeit drugs from our study of Internet-ordered Viagra is similar to the prevalence in a previous study of samples seized by authorities worldwide for suspicion of being counterfeit Viagra. Of this larger sampling, 626 were seized specifically in the United Kingdom, including 320 (51%) that were ordered via the Internet [18]. Of the Internet-ordered Viagra samples, 264 (83%) were identified as being counterfeit. The 30% to 50% API concentration in counterfeit Viagra was not surprising. Viagra and other PDE5 inhibitors seized for suspicion of being counterfeit most often have an API content significantly below the claimed or labeled amount [30], including PDE5 inhibitors ordered via the Internet [18,27]. The NABP ordered several J Sex Med **;**:**–**
B
Figure 2 Sample blister of counterfeit Viagra, including foil (A) and tablet (B) sides of packaging. Sample was assessed as being counterfeit because the cited lot number would have expired before 2009, not in 2014, low-quality printing, and a poorly rendered Pfizer logo (A); and excessively shiny foil, a poorly rendered, non–color-shifting Pfizer logo that failed authentification tests, and an incorrectly foil-colored inner “Pfizer” text of the symbol (genuine color is white; B).
U.S. Counterfeit
5 expose themselves to higher doses of unknown ingredients while trying to improve efficacy.
Figure 3 Counterfeit (left) and genuine (right) Viagra tablets. Counterfeit tablets had an excessively dark, flatfinished, non-heathered film coat; incorrect debossing fonts; and excessive weight, length, width, and thickness.
Patient Health Risks Contaminants, such as talcum powder, commercial paint, printer ink, and other active pharmaceutical entities have previously been found in counterfeit Viagra [27]; ingredients in other counterfeit PDE5 inhibitors have been deadly [29]. Our study found that counterfeit Viagra tablets were not formulated correctly. Although nongenuine “fillers” were not further assessed in this study, filler ingredients are associated with significant risk because they generally comprise the majority of tablet weight. In Canada, a 58-year-old woman died as a result of ingesting counterfeit medications [32]. Analysis revealed “dangerously high” levels of metals in her liver, including aluminum at a level 15 times higher than normal, as well as phosphorus, titanium, tin, strontium, and arsenic. She had
A
B
Figure 4 Overlay of infrared (IR) spectra from tablet cores of counterfeit (dotted line) and authentic Viagra (solid line) showing full mid-IR range (A) and expanded scale of the fingerprint region (B). Points of pattern concurrence demonstrate the presence of sildenafil citrate in the counterfeit tablets, while areas of pattern divergence demonstrate that the excipient formulation is distinctly different than genuine Viagra.
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Figure 5 Overlay of Raman spectrum of the sample (dotted line) vs. genuine (solid line) Viagra. The lack of overall pattern match demonstrates that the formulation of the subject sample does not correspond with that of authentic Viagra.
visited Internet sites peddling unlicensed pharmaceuticals and reported side effects to friends that were consistent with metal toxicity. Drugs had been purchased from an Eastern European Web site and thought to have become contaminated during subpar manufacture. This was not the first report of unsanitary places of counterfeit drug manufacture [33].
Figure 6 Overlay of core ultraviolet spectra from counterfeit sample (dotted line) vs. Viagra reference (solid line). Pattern concurrence demonstrates that the tablet core contains sildenafil, but at a considerably reduced level (approximately 35 mg/tablet, or 35% of label claim). Abs = absorbance.
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Additionally, 91% of purchases in our study did not include a PIL, which contains important contraindications to Viagra use. Missing PILs have been reported for 50% of prescription drugs ordered via the Internet [14] and for Viagra specifically [28]. More than half of 183 U.K. men in a study reported learning new information after reading the Viagra PIL, which allowed them to make appropriate health-care decisions regarding PDE5 inhibitor medication [34]. Patients with obvious contraindications to Viagra use have received online prescriptions for the drug [14,28]. By avoiding interaction with the health-care system, Internet purchasers of Viagra bypass the chance of catching these critical interactions as well as screening and treatment for comorbidities that frequently accompany ED.
Web Sites Selling POM Counterfeit ED medications are readily available from Internet sources. The percentage of online pharmacies we found that did not require a prescription for purchase of POM is the highest reported thus far; however, few previous studies specifically examined PDE5 inhibitors. Of approximately 100 Web sites assessed in a European study examining online purchase of common prescription medication, 90% did not require a prescription before dispensing [14]. Of 159 Internet sites selling controlled drugs examined by Columbia University, 85% did not require a prescription [12]; additionally, prescriptions could be faxed to the 15% of pharmacies that did require a prescription.
U.S. Counterfeit Analyses of sites selling analgesics [13] and opioids [15], medications with addictive potential, have reported similarly high percentages not requiring prescriptions (76% and 88%, respectively). Recently, an analysis of Web sites offering to supply Viagra to consumers in the United Kingdom found that of 44 unique Web sites (i.e., no “mirror” or affiliate sites were included), only three (7%) were legitimate online pharmacies [35].
Tablet Costs Tablet costs for Internet-ordered Viagra in our study were similar to those reported in previous analyses. In 1999, costs associated with ordering Viagra from 10 Internet pharmacies averaged $17.00 per tablet, ranging from $8.33–$50.00. However, this did not include shipping fees of $34.00 and possible consultation fees of $74.88 (range $65.00–$89.00) if it was determined that the prescription was “appropriate” (the patient’s medical history was allegedly reviewed by a physician before a prescription was issued) [28]. In another 1999 study that examined Internet sites selling Viagra to consumers without a prescription, average costs were $12.60 ($5–$40) for 50-mg tablets and $13.50 ($8–$50) for 100-mg tablets. Online medical evaluations were offered by 55% of sites for an average cost of $64 (range $5–$89); shipping and handling charges (ranging from $5–$48) were added by 34% of sites [36]. Neither of these studies compared costs between Internet and bricks-and-mortar pharmacies. Such costs were assessed in the Philadelphia area. Internet sites (N = 37) that provided prescription Viagra, regardless of the requirement for a prescription, had a median per-tablet price that was 22% higher than Viagra from area pharmacies. The price difference did not include shipping charges (average of $18 for U.S. sites and $8–$25 for non-U.S. sites) or an Internet physician consultation fee (median $70; range $20–$90) [37], which was 17% higher than the payment by Medicare or Philadelphia-area managed care organizations for a primary care visit. Tablet Origins The shipment origins of Internet-ordered drugs in our study varied widely. Misrepresentation of shipping country was noted in previous analyses. Web sites that sell POMs, including PDE5 inhibitors, to consumers rarely give a location [12,35,37]. Only 24% of examined sites in one study stated that medicines would be shipped from a U.S. phar-
7 macy [12], and 29% of Web sites selling Viagra were based outside of the United States in another study [36]. Alleged Canadian pharmacy sourcing was previously debunked by the FDA and confirmed in this study. U.S. consumers generally believe that properly made U.S. drugs are available more cheaply through Canadian pharmacies, therefore creating demand. Based on accompanying documentation from approximately 4,000 packages seized by the FDA from purported Canadian sources, only 15% of purchased drugs were of Canadian origin; the remaining 85% came from 27 different countries, including India, Israel, Costa Rica, and Vanuatu, and included counterfeit drugs [38]. India previously has been associated with counterfeit drugs; it is legal in India to produce APIs, and many Western countries, including the U.S. and U.K., permit personal importation of medications from countries where they can be produced legally [39]. Within China, it is also legal to manufacture generic medications [7].
Tablet Packaging Counterfeit medications were often distinguishable as suspect before chemical analysis in our study because of inferior manufacturing or inappropriate packing material. In another study of PDE5 inhibitors, some of which had been ordered via the Internet, tablets were noted to have shipped in an unlabeled plastic bag and in a plastic container with an open seal [40]; other Internet-ordered medications have been reported to arrive wrapped in newspaper or with extra, free tablets [14]. Differences in both packaging and tablet attributes between genuine and counterfeit products have been previously reported for a variety of pharmaceuticals [16,41] as well as for Viagra specifically [33]. However, packaging for PDE5 inhibitor drugs has become more sophisticated over time [42]. Experts feel that consumers are not able to distinguish counterfeit from genuine medicinal products and have themselves been fooled by good-quality imitations [14]. Caution Is Warranted Our study provides additional evidence that online sites claiming to sell authentic Viagra are not what they seem. Almost 80% of medications shipped were counterfeit, and even if medication having an authentic sildenafil formulation was received, the API was less than half the expected amount. Besides the health risks possible from ingesting J Sex Med **;**:**–**
8 counterfeit products, credit card fraud [14,28] and identity theft are also concerns with Internet ordering of medications. There is evidence that Web sites that illegally supply POM without a prescription manipulate web searching to preferentially direct consumers to their fraudulent sites. Consumers should use extreme caution when purchasing Viagra via the Internet.
Acknowledgments
The authors are grateful to John W. Thomas, Principal Scientist, and Amy Callanan, Senior Scientist, at the Pfizer Intellectual Property Forensic Laboratory in Groton, CT, USA, for their analysis of tablets purchased via the Internet. This study was sponsored by Pfizer Inc. Editorial support was provided by Tiffany Brake, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. Corresponding Author: Vera Stecher, PhD, Global Sexual Health, Pfizer Inc, 235 East 42nd St, 7th Floor, New York, NY 10017, USA. Tel: (212) 573-7405; Fax: (212) 672-7875; E-mail: Vera.Stecher@pfizer.com Disclosure/Conflict of Interest: Neil Campbell, John P. Clark, and Vera J. Stecher are Pfizer Inc employees. Irwin Goldstein reports grants/research support from Astellas, Auxilium, BioSante, Boehringer Ingelheim, Emotional Brain, Endoceutics, G & H Brands, GSK, Medtronic Vascular, Palatin, Pfizer, Slate, and Vivus; has consulted for Trimel and Vivus; and has received honoraria from Abbott, Auxilium, Coloplast, Eli Lilly, Endoceutics, GSK, and Pfizer Inc.
Statement of Authorship
Category 1 (a) Conception and Design Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (b) Acquisition of Data Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (c) Analysis and Interpretation of Data Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein
Category 2 (a) Drafting the Article Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (b) Revising It for Intellectual Content Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein J Sex Med **;**:**–**
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Neil Campbell,* John P. Clark,* Vera J. Stecher, PhD,* and Irwin Goldstein, MD† *Pfizer Inc, New York, NY, USA; †Alvarado Hospital, San Diego, CA, USA DOI: 10.1111/j.1743-6109.2012.02877.x
ABSTRACT
Introduction. Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). Methods. Pfizer monitored top search results for the query “buy Viagra” on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. Results. No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal “generic Viagra.” Cost per tablet ranged from $3.28–$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. Conclusion. Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. Campbell N, Clark JP, Stecher VJ, and Goldstein I. Internet-ordered Viagra (sildenafil citrate) is rarely genuine. J Sex Med **;**:**–**. Key Words. Counterfeit; Erectile Dysfunction; Internet; Sildenafil Citrate
Introduction
W
orldwide sales of counterfeit medicines were estimated to reach $75 billion in 2010, representing 90% growth in a 5-year period [1,2]. If past trends continue, worldwide counterfeit drug sales will increase by 25% annually [3]. In the United States, 170% more illegal pharmaceutical products were seized by the Homeland Security Department in 2010 ($5.6 million) [4] than in 2005 ($2.1 million) [5]. Although no type of pharmaceutical is immune from counterfeiting, including cancer medications [6], phosphodiesterase type 5 (PDE5) inhibitor medications have historically been targeted [7–9], likely because of stigma regarding the condition they treat, erectile dysfunction (ED) [9,10]. © 2012 International Society for Sexual Medicine
Internet purchasing has contributed to the explosive growth in counterfeit pharmaceuticals. Little money or expertise is required to create professional-looking Web sites that sell counterfeit drugs to unsuspecting consumers worldwide. A recent study by the National Association of Boards of Pharmacy (NABP) found that the vast majority of Web sites offering prescription-only medications (POMs) for sale are not legitimate [11]. Of 8,353 Internet drug outlets selling POMs, 8,034 (96%) were operating out of compliance with state and federal laws and/or NABP patient safety and pharmacy practice standards, including 6,812 that did not require a valid prescription. Similar results were reported in studies from the United States and Europe examining a variety of POMs [12–15]. J Sex Med **;**:**–**
2 The World Health Organization suggests that medicines purchased over the Internet from sites that conceal their physical address are counterfeit ⱖ50% of the time [16]; in a European study, 62% of medicines ordered via the Internet and without a prescription were substandard or counterfeit [14]. In 2004, European officials assessed that 44% of the PDE5 inhibitor sildenafil citrate (VIAGRA®, Pfizer Inc, New York, NY, USA) sold via the Internet was counterfeit [17]. In a subsequent analysis of samples seized worldwide for suspicion of being counterfeit Viagra, 83% of the samples ordered via the Internet were found to be counterfeit [18]. Last year, one in six Americans purchased prescription medicines via the Internet, meaning that 36 million consumers potentially exposed themselves to counterfeit medicines [19]. Alarmingly, European studies show that the United States is not alone in having a significant portion of the population purchase their pharmaceuticals via the Internet [18,20–22]; perceived cost and time advantages drive this behavior, even though consumers report being aware of potential danger. Recreational users and abusers of PDE5 inhibitor medication also report using the Internet as a source channel [23–25]. Counterfeits are dangerous for multiple reasons. They are not made in accordance with good manufacturing practices, and thus, are free from regulations that guarantee high-quality products [7]. They may contain inactive ingredients that can prevent the appropriate exposure to effective treatment for sometimes fatal conditions [26] or could induce buyers to overmedicate as a way to compensate for lower active drug concentration. They may contain harmful ingredients; an analysis of counterfeit Viagra revealed the presence of contaminants including talcum powder, commercial paint, and printer ink [27]. Counterfeits also may not come with important instructions regarding the use of medication [14]; patients with obvious contraindications to Viagra use have received online prescriptions for the drug [14,28]. Patients who buy counterfeit drugs avoid interaction with the health-care system; in the case of ED, patients deprive themselves of needed screening or treatment for conditions which frequently accompany ED, including diabetes and heart disease [7]. People have died from using counterfeit medications [16], including counterfeit PDE5 inhibitors [29]. This study assessed the requirements for purchase, cost, origin, and content of medications sold J Sex Med **;**:**–**
Campbell et al. via the Internet and purporting to be the PDE5 inhibitor Viagra.
Methods
Procurement Pfizer Global Security monitored top search results for the phrase “buy Viagra” on the leading two Internet search engines from March 14–18, 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Authenticity Evaluation Packaging and tablet attributes of ordered medicines were evaluated by visual and physical methods. Tablets were assessed for chemical composition using Raman and infrared spectroscopic analyses to assess conformance of tablet coating and tablet core formulations to authentic Viagra formulations. Ultraviolet spectroscopic and liquid chromatography/mass spectroscopic analyses were used to assess the content of sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra. All analyses were performed at the Pfizer Intellectual Property Forensic Laboratory in Groton, CT, USA.
Results
Of the 22 Web sites assessed, 100% did not ask for a prescription before purchase as required by law (Table 1); none required a completed health screening to enable purchase. Additionally, 91% of the sites tested claimed to sell medicines identified as “generic Viagra,” which is not approved by the U.S. Food and Drug Administration (FDA). Cost per tablet ranged from $3.28–$33.00. Shipment origins of ordered products were most commonly Hong Kong (N = 11 Web sites), the United States (N = 6), and the United Kingdom (N = 2); others were Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Counterfeit medications were often distinguishable as suspect before tablet analysis. Packaging differed from that of genuine Viagra; blisters occasionally shipped wrapped in magazines or aluminum foil (Figure 1). Blisters were not intact on five samples (19%) assessed (Table 1). Common shortcomings of counterfeit packaging included cited lot
3
U.S. Counterfeit Table 1
Analysis of ordering and products received from 22 unique Web sites purporting to sell Viagra
Web site http://www.accessrx.com http://www.onlinepharmacycr.com http://www.atlanticdrugs.com http://www.topills.com http://www.videochron.com http://www.erectiledysfunction-pills.com http://www.directpharma.net http://www.buyingviagra.us http://www.gerryggriffin.com/viagra http://www.v-medical.com/viagra.html http://www.buyviagra4you.com http://www.doctor-approved.org http://www.viagra.gd http://www.viagrabuy.cc http://www.viagra.ac http://fr.pharm4all.com http://de.pharm4all.com http://www.buyviagra1.com http://www.adventuregamingstl.org/ viagra.aspx http://www.buy-viagra-online.me.uk http://www.medical-place.com http://www.buy-viagra.co
Prescription required?
Price per tablet ($)
Postal origin
PI sheet included?
Blister intact on all tablets?
Test result
API (%)
No No No No No No No No No No No No No No No No No No No
29.67 5.95 33.00 12.50 3.28 15.63 11.20 9.06 8.66 12.10 12.90 5.10 9.06 9.15 12.50 21.75 18.50 7.37 12.50
United States United States United States Canada India China Hong Kong Hong Kong Hong Kong United States Hong Kong Hong Kong Hong Kong United States Hong Kong United Kingdom United Kingdom United States Hong Kong
No No No No No No No No No No No No No No No Yes Yes No No
Yes Yes * No Yes Yes No Yes Yes No No Yes Yes No Yes Yes Yes Yes Yes
Authentic Counterfeit Authentic Counterfeit Illegal generic Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Counterfeit Authentic Authentic Counterfeit Counterfeit
N/A 30 N/A 40 N/A 35 35 45 30 30 30 30 40 50 35 N/A N/A 30 40
No No No
10.61 12.50 16.13
Hong Kong Hong Kong Hong Kong
No No No
Yes Yes Yes
Counterfeit Counterfeit Counterfeit
35 35 30
*Not a blister; received as a vial of three loose tablets API = active pharmaceutical ingredient; N/A = not applicable; PI = product information
numbers corresponding to expired products (e.g., 314833021), low-quality printing on the logo side of the foil, a poorly rendered Pfizer logo on the foil side (a non–color-shifting Pfizer logo or inner Pfizer text being foil colored instead of white), and excessively shiny foil on the tablet side of the blister (Figure 2). Shipped medications often lacked the product information leaflet (PIL) required to accompany genuine Viagra (only two shipments [9%] included a genuine PIL; Table 1). Counterfeit tablets generally had similar appearances as genuine Viagra (Figure 3), easily mimicking the blue diamond shape, but often without accurate coloration or logo debossing. A total of 22 sample tablets were analyzed after receipt (Table 1). Seventeen (77%) were counterfeit (Figure 4), four (18%) were authentic, and one (5%) was an illegal generic. Tablet core (Figure 5) and coating (data not shown) formulations did not match those of authentic Viagra. Authentic medications were shipped from the United States and the United Kingdom; the illegal generic shipped from India. The 17 counterfeit samples were analyzed for sildenafil citrate content. API contents varied between 30% and 50% of the label claim (Figure 6). The price per tablet for counterfeits was intermediate to the generic, which was the
cheapest, and authentics, which were the most expensive. Discussion
Unauthorized sales of prescription medication have become rampant, amplified by convenient Internet access and multiple purchasing options. In this study, Internet sites claiming to sell authentic Viagra medication shipped counterfeit medication 77% of the time, and these counterfeits contained only 30% to 50% of the labeled API claim. Our study, which used a prospective assessment of Web sites claiming to sell Viagra, differed from previous studies, which examined the prevalence of counterfeit medications by assessing samples seized by authorities for suspicion of being counterfeit Viagra [18,27]. In seized-sample analyses, some quality of the samples alerted authorities to possible fraud, perhaps contributing to the high percentage of counterfeits encountered. Here, we ordered medications from the most common Web sites returned from popular Internet search engines, meant to simulate the way a patient might research the acquisition of Viagra via the Internet, and still found that an alarmingly high percentage were counterfeit. Caution is warranted when purchasing Viagra through the Internet, even if shipped from within the United States. J Sex Med **;**:**–**
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different medications, including the PDE5 inhibitor Cialis (tadalafil, Lilly USA, Indianapolis, IN, USA), from 13 suspicious Web sites selling POM without a prescription [31]. Testing by the FDA found wide variation in the amount of API present in drugs received, ranging from none to far exceeding labeled doses; regulatory analysis by the drug manufacturer found that they did not meet the company’s U.S. standards [31]. In the U.K. study cited earlier [18], 55 of the 264 Internet-ordered samples were analyzed chemically. Just 16% fell within the regulatory threshold of 5% of labeled sildenafil concentration; 25% contained no sildenafil. Only 2% of samples had API concentration that exceeded the labeled dose of sildenafil. Unfortunately, lowered APIs create the potential that patients could A
B
Figure 1 Counterfeit Viagra packaging. Blisters and blister segment (cutout), as received wrapped in glossy paper (A); loose tablets in plastic wrap (B).
Prevalence and Sildenafil Content of Counterfeit Viagra on the Internet The 77% incidence of counterfeit drugs from our study of Internet-ordered Viagra is similar to the prevalence in a previous study of samples seized by authorities worldwide for suspicion of being counterfeit Viagra. Of this larger sampling, 626 were seized specifically in the United Kingdom, including 320 (51%) that were ordered via the Internet [18]. Of the Internet-ordered Viagra samples, 264 (83%) were identified as being counterfeit. The 30% to 50% API concentration in counterfeit Viagra was not surprising. Viagra and other PDE5 inhibitors seized for suspicion of being counterfeit most often have an API content significantly below the claimed or labeled amount [30], including PDE5 inhibitors ordered via the Internet [18,27]. The NABP ordered several J Sex Med **;**:**–**
B
Figure 2 Sample blister of counterfeit Viagra, including foil (A) and tablet (B) sides of packaging. Sample was assessed as being counterfeit because the cited lot number would have expired before 2009, not in 2014, low-quality printing, and a poorly rendered Pfizer logo (A); and excessively shiny foil, a poorly rendered, non–color-shifting Pfizer logo that failed authentification tests, and an incorrectly foil-colored inner “Pfizer” text of the symbol (genuine color is white; B).
U.S. Counterfeit
5 expose themselves to higher doses of unknown ingredients while trying to improve efficacy.
Figure 3 Counterfeit (left) and genuine (right) Viagra tablets. Counterfeit tablets had an excessively dark, flatfinished, non-heathered film coat; incorrect debossing fonts; and excessive weight, length, width, and thickness.
Patient Health Risks Contaminants, such as talcum powder, commercial paint, printer ink, and other active pharmaceutical entities have previously been found in counterfeit Viagra [27]; ingredients in other counterfeit PDE5 inhibitors have been deadly [29]. Our study found that counterfeit Viagra tablets were not formulated correctly. Although nongenuine “fillers” were not further assessed in this study, filler ingredients are associated with significant risk because they generally comprise the majority of tablet weight. In Canada, a 58-year-old woman died as a result of ingesting counterfeit medications [32]. Analysis revealed “dangerously high” levels of metals in her liver, including aluminum at a level 15 times higher than normal, as well as phosphorus, titanium, tin, strontium, and arsenic. She had
A
B
Figure 4 Overlay of infrared (IR) spectra from tablet cores of counterfeit (dotted line) and authentic Viagra (solid line) showing full mid-IR range (A) and expanded scale of the fingerprint region (B). Points of pattern concurrence demonstrate the presence of sildenafil citrate in the counterfeit tablets, while areas of pattern divergence demonstrate that the excipient formulation is distinctly different than genuine Viagra.
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Figure 5 Overlay of Raman spectrum of the sample (dotted line) vs. genuine (solid line) Viagra. The lack of overall pattern match demonstrates that the formulation of the subject sample does not correspond with that of authentic Viagra.
visited Internet sites peddling unlicensed pharmaceuticals and reported side effects to friends that were consistent with metal toxicity. Drugs had been purchased from an Eastern European Web site and thought to have become contaminated during subpar manufacture. This was not the first report of unsanitary places of counterfeit drug manufacture [33].
Figure 6 Overlay of core ultraviolet spectra from counterfeit sample (dotted line) vs. Viagra reference (solid line). Pattern concurrence demonstrates that the tablet core contains sildenafil, but at a considerably reduced level (approximately 35 mg/tablet, or 35% of label claim). Abs = absorbance.
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Additionally, 91% of purchases in our study did not include a PIL, which contains important contraindications to Viagra use. Missing PILs have been reported for 50% of prescription drugs ordered via the Internet [14] and for Viagra specifically [28]. More than half of 183 U.K. men in a study reported learning new information after reading the Viagra PIL, which allowed them to make appropriate health-care decisions regarding PDE5 inhibitor medication [34]. Patients with obvious contraindications to Viagra use have received online prescriptions for the drug [14,28]. By avoiding interaction with the health-care system, Internet purchasers of Viagra bypass the chance of catching these critical interactions as well as screening and treatment for comorbidities that frequently accompany ED.
Web Sites Selling POM Counterfeit ED medications are readily available from Internet sources. The percentage of online pharmacies we found that did not require a prescription for purchase of POM is the highest reported thus far; however, few previous studies specifically examined PDE5 inhibitors. Of approximately 100 Web sites assessed in a European study examining online purchase of common prescription medication, 90% did not require a prescription before dispensing [14]. Of 159 Internet sites selling controlled drugs examined by Columbia University, 85% did not require a prescription [12]; additionally, prescriptions could be faxed to the 15% of pharmacies that did require a prescription.
U.S. Counterfeit Analyses of sites selling analgesics [13] and opioids [15], medications with addictive potential, have reported similarly high percentages not requiring prescriptions (76% and 88%, respectively). Recently, an analysis of Web sites offering to supply Viagra to consumers in the United Kingdom found that of 44 unique Web sites (i.e., no “mirror” or affiliate sites were included), only three (7%) were legitimate online pharmacies [35].
Tablet Costs Tablet costs for Internet-ordered Viagra in our study were similar to those reported in previous analyses. In 1999, costs associated with ordering Viagra from 10 Internet pharmacies averaged $17.00 per tablet, ranging from $8.33–$50.00. However, this did not include shipping fees of $34.00 and possible consultation fees of $74.88 (range $65.00–$89.00) if it was determined that the prescription was “appropriate” (the patient’s medical history was allegedly reviewed by a physician before a prescription was issued) [28]. In another 1999 study that examined Internet sites selling Viagra to consumers without a prescription, average costs were $12.60 ($5–$40) for 50-mg tablets and $13.50 ($8–$50) for 100-mg tablets. Online medical evaluations were offered by 55% of sites for an average cost of $64 (range $5–$89); shipping and handling charges (ranging from $5–$48) were added by 34% of sites [36]. Neither of these studies compared costs between Internet and bricks-and-mortar pharmacies. Such costs were assessed in the Philadelphia area. Internet sites (N = 37) that provided prescription Viagra, regardless of the requirement for a prescription, had a median per-tablet price that was 22% higher than Viagra from area pharmacies. The price difference did not include shipping charges (average of $18 for U.S. sites and $8–$25 for non-U.S. sites) or an Internet physician consultation fee (median $70; range $20–$90) [37], which was 17% higher than the payment by Medicare or Philadelphia-area managed care organizations for a primary care visit. Tablet Origins The shipment origins of Internet-ordered drugs in our study varied widely. Misrepresentation of shipping country was noted in previous analyses. Web sites that sell POMs, including PDE5 inhibitors, to consumers rarely give a location [12,35,37]. Only 24% of examined sites in one study stated that medicines would be shipped from a U.S. phar-
7 macy [12], and 29% of Web sites selling Viagra were based outside of the United States in another study [36]. Alleged Canadian pharmacy sourcing was previously debunked by the FDA and confirmed in this study. U.S. consumers generally believe that properly made U.S. drugs are available more cheaply through Canadian pharmacies, therefore creating demand. Based on accompanying documentation from approximately 4,000 packages seized by the FDA from purported Canadian sources, only 15% of purchased drugs were of Canadian origin; the remaining 85% came from 27 different countries, including India, Israel, Costa Rica, and Vanuatu, and included counterfeit drugs [38]. India previously has been associated with counterfeit drugs; it is legal in India to produce APIs, and many Western countries, including the U.S. and U.K., permit personal importation of medications from countries where they can be produced legally [39]. Within China, it is also legal to manufacture generic medications [7].
Tablet Packaging Counterfeit medications were often distinguishable as suspect before chemical analysis in our study because of inferior manufacturing or inappropriate packing material. In another study of PDE5 inhibitors, some of which had been ordered via the Internet, tablets were noted to have shipped in an unlabeled plastic bag and in a plastic container with an open seal [40]; other Internet-ordered medications have been reported to arrive wrapped in newspaper or with extra, free tablets [14]. Differences in both packaging and tablet attributes between genuine and counterfeit products have been previously reported for a variety of pharmaceuticals [16,41] as well as for Viagra specifically [33]. However, packaging for PDE5 inhibitor drugs has become more sophisticated over time [42]. Experts feel that consumers are not able to distinguish counterfeit from genuine medicinal products and have themselves been fooled by good-quality imitations [14]. Caution Is Warranted Our study provides additional evidence that online sites claiming to sell authentic Viagra are not what they seem. Almost 80% of medications shipped were counterfeit, and even if medication having an authentic sildenafil formulation was received, the API was less than half the expected amount. Besides the health risks possible from ingesting J Sex Med **;**:**–**
8 counterfeit products, credit card fraud [14,28] and identity theft are also concerns with Internet ordering of medications. There is evidence that Web sites that illegally supply POM without a prescription manipulate web searching to preferentially direct consumers to their fraudulent sites. Consumers should use extreme caution when purchasing Viagra via the Internet.
Acknowledgments
The authors are grateful to John W. Thomas, Principal Scientist, and Amy Callanan, Senior Scientist, at the Pfizer Intellectual Property Forensic Laboratory in Groton, CT, USA, for their analysis of tablets purchased via the Internet. This study was sponsored by Pfizer Inc. Editorial support was provided by Tiffany Brake, PhD, at Complete Healthcare Communications, Inc., and was funded by Pfizer Inc. Corresponding Author: Vera Stecher, PhD, Global Sexual Health, Pfizer Inc, 235 East 42nd St, 7th Floor, New York, NY 10017, USA. Tel: (212) 573-7405; Fax: (212) 672-7875; E-mail: Vera.Stecher@pfizer.com Disclosure/Conflict of Interest: Neil Campbell, John P. Clark, and Vera J. Stecher are Pfizer Inc employees. Irwin Goldstein reports grants/research support from Astellas, Auxilium, BioSante, Boehringer Ingelheim, Emotional Brain, Endoceutics, G & H Brands, GSK, Medtronic Vascular, Palatin, Pfizer, Slate, and Vivus; has consulted for Trimel and Vivus; and has received honoraria from Abbott, Auxilium, Coloplast, Eli Lilly, Endoceutics, GSK, and Pfizer Inc.
Statement of Authorship
Category 1 (a) Conception and Design Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (b) Acquisition of Data Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (c) Analysis and Interpretation of Data Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein
Category 2 (a) Drafting the Article Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein (b) Revising It for Intellectual Content Neil Campbell; John P. Clark; Vera J. Stecher; Irwin Goldstein J Sex Med **;**:**–**
Campbell et al.
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