key: cord-1002099-73ohfbn7
authors: Sansone, Andrea; Cuzin, Béatrice; Jannini, Emmanuele A.
title: Facing Counterfeit Medications in Sexual Medicine. A Systematic Scoping Review on Social Strategies and Technological Solutions
date: 2021-10-04
journal: Sex Med
DOI: 10.1016/j.esxm.2021.100437
sha: 772f7d1eb1d4da4e3fce26fce8443de74fe574a6
doc_id: 1002099
cord_uid: 73ohfbn7

INTRODUCTION: The counterfeit phenomenon is a largely under-reported issue, with potentially large burden for healthcare. The market for counterfeit drugs used in sexual medicine, most notably type 5 phosphodiesterase inhibitors (PDE5i), is rapidly growing. AIMS: To report the health risks associated with the use of counterfeit medications, the reasons driving their use, and the strategies enacted to contain this phenomenon. METHODS: A systematic scoping review of the literature regarding counterfeit PDE5i was carried between January and June 2021, then updated in August 2021. MAIN OUTCOME MEASURE: We primarily aimed to clarify the main drivers for counterfeit PDE5i use, the health risks associated, and the currently available strategies to fight counterfeiters. RESULTS: One hundred thirty-one records were considered for the present scoping review. Production of fake PDE5i is highly lucrative and the lacking awareness of the potential health risks makes it a largely exploitable market by counterfeiters. Adulteration with other drugs, microbial contamination and unreliable dosages make counterfeit medications a cause of worry also outside of the sexual medicine scope. Several laboratory techniques have been devised to identify and quantify the presence of other compounds in counterfeit medications. Strategies aimed at improving awareness, providing antitampering packaging and producing non-falsifiable products, such as the orodispersible formulations, are also described. CLINICAL IMPLICATIONS: Improving our understanding of the PDE5i counterfeit phenomenon can be helpful to promote awareness of this issue and to improve patient care. STRENGTHS & LIMITATIONS: Despite the systematic approach, few clinical studies were retrieved, and data concerning the prevalence of counterfeit PDE5i use is not available on a global scale. CONCLUSION: The counterfeit phenomenon is a steadily growing issue, with PDE5i being the most counterfeited medication with potentially large harmful effects on unaware consumers. Sansone A, Cuzin B, and Jannini EA. Facing Counterfeit Medications in Sexual Medicine. A Systematic Scoping Review on Social Strategies and Technological Solutions. Sex Med 2021;9:100437.

The efficacy of type 5 phosphodiesterase inhibitors (PDE5i) has been verified by countless studies, and indeed these drugs have been included as the first-line treatment for the management of erectile dysfunction (ED). 1 It is therefore unsurprising that the general population has heard about these drugs, including patients with a very limited awareness of their sexual health. However, the widespread knowledge of these drugs in media and social networks 2 has made them widely adopted lifestyle drugs, 3 thus drawing the attention of counterfeiters.

The exact meaning of "counterfeit medicine" has been disputed in the last decades. The definition proposed by the World Health Organization (WHO) in 2009, which defined such drugs as "deliberately and fraudulently mislabeled with respect to identity and/or source", was recently revised in 2017, with an added warning concerning the exact composition of the drug ("deliberately or fraudulently misrepresent their identity, composition or source"). 4 The WHO also proposed the definition of "substandard" drugs for all those products that are authorized on a local basis but fail to meet quality standards for or specifications. 4 While theoretically these definitions could be helpful in the identification of products of dubious origin, they have not been universally accepted, and there seems to be no worldwide policy aimed to fight the ever-increasing phenomenon of counterfeiting. National regulatory agencies have seldom joined efforts on an international scale, and the consequences for counterfeiters are generally less severe than one would expect. 5−8 For practical purposes, counterfeit drugs are those without any active pharmaceutical ingredients (APIs), or with different dosages of the intended APIs, or with fake packaging. Such drugs often include other pharmaceutical products than those intended, possibly increasing the health risks of consumers. 9 In this scenario, experts in sexual medicine and andrologists should not underestimate the phenomenon of counterfeit medications. Counterfeit drugs used to improve sexual function represent a growing issue for public health, and while several strategies have been developed to fight counterfeiters, the market is constantly increasing. In the present systematic scoping review, we aimed to provide a thorough overview of the extent of this problem, answering the following questions: why do patients choose to actively look for counterfeit products, rather than following the traditional complaint-diagnosis-therapy track? What are the risks associated with counterfeit medications, and particularly with counterfeit PDE5i? Which are the possible strategies to prevent these risky behaviors?

We systematically reviewed all publications found on PubMed and Google Scholar using the following search string: (pde5 or phosphodiesterase or sildenafil or tadalafil or vardenafil or avanafil) and (fake or counterfeit or falsified). The initial systematic search was performed between January and June 2021, and a subsequent update was performed in August 2021. Results were limited to full articles written in English and/or Italian, without any date limitation and with no additional inclusion or exclusion criteria. The search string was purposely vague in order to adequately perform a scoping review − that is, "to identify knowledge gaps, scope a body of literature, clarify concepts or to investigate research conduct". 10 References of included papers were also scanned looking for additional content which would have been otherwise missed by our search queries. We also searched among reports by Organizations and Regulatory Agencies, such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), and World Health Organization (WHO) in order to retrieve additional material concerning the topic of counterfeit medical products, including, but not limited to, PDE5i.

As shown in Figure 1 , following removal of duplicate results, 202 unique record were thus found, among which 12 were not assessed due to language constraints, 18 had no full-text available (including 5 conference abstracts) and 5 were not research papers (one conference program, one application note, and three investigation reports). One hundred sixty-seven full texts were thus evaluated, and 36 papers were considered off-topic for the present study. The remaining 131 papers and book chapters were considered for the present scoping review: among these results, 96 investigated available techniques for the analysis of counterfeit medical products, 5,11−105 6 were case reports 53,92,106−109 (two of which also provided information on chemical analysis of the counterfeit drug), 7 were editorials, 7,110−115 22 were reviews or guidelines, 6,8,9,116−134 and 2 studies reported patterns of use of counterfeit drugs in two different countries, namely a retrospective study in Brazil 135 and a prospective study in Japan. 136 According to our results, we identified the following four main topics for research: worldwide prevalence of counterfeit products, including PDE5i; health risks associated with the use of counterfeit PDE5i and other pro-erectile medications; social and psychological reasons for the counterfeit PDE5i phenomenon; and strategies to fight counterfeiting in sexual medicine ( Figure 2 ).

The Numbers of the Counterfeits in the World.

Drug counterfeiting has been a known phenomenon for many centuries, with reports of fake antimalarial drugs being sold since the 17th century. 9 The real extent of counterfeit drugs being presently produced and sold is impossible to ascertain, 112, 115, 117, 124, 125 and even countries with no reported findings of counterfeited products are virtually non-exempt from this issue. The most recent WHO Global Surveillance and Monitoring System (GSMS) report on substandard and falsified medical products 4 highlights several factors limiting the reporting of inadequate products, such as low detection levels, cultural reasons to refrain from reporting, and the already mentioned blurry definition of counterfeit products in several countries. As an example, no reports were addressed between 2013 and 2017 to the WHO GSMS by many countries, including Canada, Portugal, and Australia: however, this is not an indication of no counterfeit medications being illegally sold, but rather that no reports were escalated to the WHO, possibly being investigated and managed internally. Furthermore, as counterfeit products are generally produced abroad and sold through the internet, 125 reports are closer to a depiction of the international situation than to the snapshot of the reporting country. 65 It is also worth mentioning that in order to adequately address the issue of counterfeit medications, the involvement of several authorities (e.g. customs offices and police, but also healthcare professionals) actively searching for counterfeit products is necessary 114 : quoting the WHO GSMS, "The more one looks, the more one finds". 4 The African region accounts for almost 42% of the reports addressed to the WHO GSMS between 2013 and 2017, 4 with antibiotics and antimalarials being the most counterfeited medical products, due to the high request in low-income, developing countries. 15, 130, 133 In many cases, individuals in poor economic conditions prefer to buy drugs at a cheaper price, despite being aware of the potential risks to their health, under the assumption that they would be better than the absence of any treatment whatsoever. 9 In some emerging countries, the prevalence of counterfeit drugs is estimated to be reaching up to 60%. 121 Lifestyle drugs are the most counterfeited products found by police investigations in developed countries, such as in Europe and North America, with PDE5i having the largest share of the market and other appearance and performance enhancing drugs, such as anabolic androgen steroids, being close second. 65, 73, 125, 126, 135 For the largest part, the high prevalence of counterfeit PDE5i can be related to the well-known efficacy of these drugs, their supposed safety, and their commercial success. 45, 126 Indeed, analysis of urban wastewater showed that in some European cities the concentration of sildenafil and its urinary metabolites was significantly higher than expected based on prescriptions, suggesting large illegal sources of drug acquisition. 70 While the FDA reports incidence of counterfeit drugs in the United States to be rare, relatively to the large number of prescription drugs used, 137 the amount of investigations due to drug fraud have been on the rise at least since 2000. 8 In Europe, almost 36 million counterfeited sildenafil tablets were sold between 2004 and 2008, 6 and in 2010 up to 2.5 million men were likely assuming "fake" sildenafil tablets, accounting for about 50% of its total use. 8 In Brazil, 80% of reports in regards to counterfeit drugs between 2007 and 2010 included counterfeit sildenafil or tadalafil 135 ; in Japan, where men with ED can legally buy medications from abroad for private use, the online market for counterfeit PDE5i has grown exponentially, with reports from 2010 describing the market for counterfeits PDE5i being 2.5 larger than that of genuine PDE5i. 120, 136 PDE5i are an extremely lucrative market for counterfeiters, as the revenue is estimated to be up to 2000 higher than that of cocaine while having much lower risks for the producers. [5] [6] [7] [8] 124 The Risks of the Black Market for the Unaware User

The use of counterfeit medical products carries a significant risk for the user's health, due to several factors which are not always immediately obvious to the consumers themselves.

First and foremost, the largest health threats come from the use of wrong dosages of the intended drug − either too low to be effective, or at excessively high and possibly toxic levels, with large variations in drug contents. 6, 59, 67, 125, 129 The risk of overdosage of the medication is also possible for products with low content of the API, as consumers might be taking more than one tablet to achieve the desired effect. 6, 18 However, in order to generate revenue and refrain the buyer to search for more efficacious products, counterfeiters are generally likely to use include the main API or similar active ingredients, or, as reported below, to add other APIs aiming to increase the efficacy. 7 Counterfeit products are often produced in poor quality laboratories, resulting in the presence of residual solvents and contaminants in the finished product. 6, 45, 62, 125, 128, 129 An analysis of counterfeited or illegal PDE5i collected between 2005 and 2011 in Italy reported that excipients were different than expected from a genuine product in 80% of analyzed samples, with presence of potentially toxic compounds in 17% of tablets. 19 These substances include ethanol, acetone, tetrachloromethane and dicloromethane 63 as well as paints and printer inks, 8 potentially harmful to the consumers as well as to the environment. Salts and compounds used during the preparation of the drugs can alter the pharmacodynamic properties of the main API, 91 and in some cases can act as APIs on their own, as reported for 2-Mercaptobenzothiazolecontaminated sildenafil tablets. 26 Another potential risk comes from the use of different APIs in the preparation of the counterfeited product, either voluntarily, in order to increase efficacy, 59 or involuntarily, following inadequate quality control. For treatments used in sexual medicine, agents voluntarily added to increase efficacy include different drugs belonging to the same family (eg, vardenafil being added to sildenafil tablets 40 ), or drugs potentially "synergistic" to the main product (eg, sildenafil being added to dapoxetine tablets 57 ). While in theory the effects of the combined drugs might lead to increased efficacy, the risk of developing side effects is similarly increased; additionally, the association of these drugs is not recommended by any of the regulatory agencies or guidelines. 117, [138] [139] [140] [141] [142] PDE5i can also be added to "sexual enhancement" herbal remedies in order to increase the efficacy of the products 6, 30, 47, 76, 79, 116, 118 : as an example, a herbal remedy sold as a "sexual enhancer" was found out to contain sildenafil and tadalafil in dosages up to 200 times the suggested dose. 106 Such high dosages, together with the presence of toxic solvents, are possibly leading to harmful effects for the unsuspecting user: indeed, acute liver injury and ischemic stroke have been reported following the intake of herbal remedies contaminated by sildenafil and/or tadalafil. 108, 122, 128 Likewise, analogues of PDE5i have been added to "functional foods" (eg, pseudovardenafil and hydroxyvardenafil in dietary supplements 79 ) and counterfeit medications (eg, hongdenafil, homosildenafil and hydroxyhomosildenafil in counterfeit sildenafil 82 ) to enhance the effects: safety and efficacy profiles of such substances have not been adequately investigated, possibly resulting in hazardous effects for the unaware user. Similar considerations can be made for dietary supplements sold with the claim to improve sexual health, whose adulteration can pose a risk to consumers' health. 23, 128 On the other hand, adulteration with other APIs not intended to be included in the product has the potential to generate unwanted side effects according to the contaminating drug. A clear picture of the potential risks associated with the use of contaminated drugs comes from an outbreak of hypoglycemia occurring in 2008 in Singapore: 150 nondiabetic men were admitted to public hospitals for hypoglycemia due to adulteration of both counterfeit tadalafil tablets and herbal remedies with glibenclamide, with lethal outcome for four of the involved consumers. 143 Following this first episode, several other occurrences of contamination with glibenclamide has been reported for both counterfeit PDE5i medications 53 and herbal remedies. 107, 109 Adulteration of PDE5i with paracetamol or metronidazole 8 has similarly been reported. This phenomenon is not limited to drugs or remedies being taken to improve male sexual health: contamination of slimming products, skin creams, and analgesics 38 has also been reported, with orlistat, sibutramine, corticosteroids, and other appearance and performance enhancing drugs being added without being declared. Herbal supplements containing flibanserin and tadalafil have also been identified. 75 In some cases, the adulteration is seemingly accidental and a consequence of inappropriate laboratory procedures, as occurring with glibenclamide, although in many situations the inclusion of another API is voluntarily performed to enhance the efficacy of the treatment. Given that most, if not all, classes of medication are able to exert a tangible effect on sexual health − antidepressants, antihypertensives and opioids being known examples of this phenomenon − the issue of drug adulteration is extremely relevant for sexual medicine specialists. 6, 113, 115 Microbial growth resulting from production of the counterfeited drug in nonsterile laboratories has also been reported. 69 Several bacteria able to cause infection, among which the most common were from the Bacillus genus, were identified: on the other hand, genuine products do not show signs of contamination. 69 This difference is hardly surprising, giving the strict good manufacturing practices required by regulatory agencies for the authorization and licensing of medical products and the generally poor hygienic conditions of clandestine laboratories. 6, 9, 65, 69 Health Risks of Unsupervised Use of Counterfeit PDE5i

Another issue, largely unrecognized by most subjects buying counterfeit products online, lies in the unsupervised use of the intended API. Concerning treatments for sexual dysfunctions, while PDE5i have a generally good safety profile, clinicians prescribing these drugs should be well aware of the potential contraindications in selected patients, such as those undergoing nitrate therapies: individuals buying these drugs online might not be aware of the potential risks associated with other concomitant treatments. 112, 115 Cases of sexual activity related deaths have also been reported due to nonprescription use of PDE5i in high-risk patients, partly because of underlying conditions, and partly because of the use of combined use of multiple PDE5i. 144 Some websites only provide high dosages of PDE5i, without mentioning the suggested "starting" dose for any naïve patient. 57 Additionally, first-line treatments for ED include pursuing a healthier lifestyle, such as by limiting alcohol intake, reducing harm from tobacco smoking and performing physical exercise 112, 145, 146 : individuals buying "sexual enhancers" online, or getting them from friends without any prior clinical evaluation, are generally less aware of the pathophysiology of sexual dysfunctions 115 and thus less likely to investigate for any underlying condition, such as endocrine dysfunctions including hypogonadism 147, 148 and diabetes, 138, 149, 150 or metabolic and cardiovascular diseases, 150−152 possibly resulting in ED. 136, 153 The unsupervised use of PDE5i might therefore reduce the rate of diagnosis for ED-associated diseases. 8, 115, 154 Worryingly, this phenomenon is not limited to drugs for sexual dysfunctions: indeed, several reports suggest that internet can be used in order to circumvent doctors' opinions and consultations also concerning other conditions. 7, 8 Another fundamental professional help is skipped when buying online counterfeit PED5is, that is, that one from the pharmacist. 123 The selling of sildenafil out of the counter in countries as United Kingdom and Norway ensured a higher degree of accuracy and specificity in the patient and pharmacist decision-making around suitability for use. 155 Moreover, it could be inferred that the peculiar pharmacist-client relationship may result in a more "horizontal" than "vertical" information which is to be bona fide considered particularly efficient when complex therapeutical strategies, such as changes in lifestyle, have to be prescribed. 123 However, a recent online survey on 668 Italian pharmacists demonstrated that they have limited knowledge about falsified drugs in general, with only 24.5% of respondents failing to indicate that falsified drugs may contain less or different ingredients, 46.4% less and/or different excipients, and 72.3% ignoring that falsified drugs may be lethal. 156 One in 3 respondents did not know about falsified drugs in Italy. These findings demonstrated that, without targeted, continuous and strong educational interventions the pharmacists' community could be hardly considered a resource against the risk of counterfeits in the field of ED treatment. 123 The need of specific education of the pharmacist in identifying falsified medicines has been found as a major strategy also in United Kingdom. 157 Additionally, while buyers are often enticed by the possibility of getting the desired drug at a cheaper price, this is rarely the case, due to several "hidden" costs, including shipment, customs clearance, online medical consultations, additional packaging and so forth 112 ; additionally, in the case that no products are received by the buyer, there is little, if any at all, chance to retrieve all money spent. This is, of course, on top of the potential risks associated with sharing payment information on "shady" websites, such as "phishing" and other forms of digital threats.

From a distance, it would be easy to identify 2 categories of "victims" of counterfeit drugs: patients who receive a prescription from a healthcare specialist and look for cheaper alternatives to pharmacies and individuals who seek treatments without any prior consultation. 7 This generalization is fitting for all kinds of counterfeit medications, not being limited to drugs for sexual dysfunction only 7 : however, several factors contribute to the ever-growing market for falsified PDE5i. 112, 121 First and foremost, as previously reported, the high success of the genuine drugs made them quite recognized even to the general population and widely adopted worldwide. 116, 121, 129 ED is a frequent complaint in aging men, 158 and it is largely expected that many elderly people would look for treatment in order to improve their sexual health; however, there is compelling evidence that some individuals would take such drugs for recreational purposes in the absence of medical suggestion, even among younger men. 129, 136, [159] [160] [161] [162] Considering the social stigma for ED, it is unsurprising that many subjects would prefer buying online, in full anonymity, rather than buying in person 18, 65, 117, 129 : indeed, PDE5i have the highest prevalence among drugs bought through the internet, 8, 125, 129 and younger subjects are indeed those who buy drugs online more frequently. 112 Additionally, most fraudulent websites do not require prescriptions, 65 nor do they provide "remote" medical consultations. 8 The convenience of being able to buy the drugs at every time of the day and from mobile devices is another possible reason driving people towards online pharmacies or pseudo-pharmacies, 116 and in more recent days also toward other markets, such as social media. 2, 113 Additionally, as the costs of these drugs are among the chief reasons for drop-out, 131, 163 it is unsurprising that consumers might be looking for cheaper alternatives.

Herbal remedies are often promoted as "natural" supplements to improve sexual health, therefore giving to the unaware user the false perception of a safer and more reliable product with no side effects. 6, 43, 116, 128 Once again, adulteration with PDE5i − performed in order to provide some effects, and hence generate repeat business 7 − makes the use of these products quite unsafe for consumers, who might develop severe side effects with little awareness of the medications they're involuntarily taking. Additionally, although several well conducted in vitro and in vivo studies demonstrated a role of herbal remedies in the management of male sexual health, 164−169 the potential effects of these remedies are largely disputed. 116 While this is a relatively smaller phenomenon, some reports of counterfeit drugs being legally sold has been collected, 73, 111 highlighting the potential of counterfeit products to reach the "regular" supply chain. It is, therefore, necessary to educate potential consumers in order to prevent them from falling prey to counterfeiters.

It is not uncommon for patients to ask for compounded medications, that is, drugs prepared in a pharmacy laboratory by trained professionals; such products are clearly different from counterfeit medication, being the application of pharmaceutical expertise to provide tailored treatment. Historically, drug manufacture and preparation were among the chief tasks for a pharmacist in the past. As of today, the need for higher quality standards and for mass production has moved this process from pharmacies to industries; however, compounded medications are still prepared for tailored treatment of patients with particular needs. The FDA defines drug compounding as "the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient". 170 In Europe, the term "pharmacy preparation" is also used; European laws distinguish the 'magistral formula' ("any medicinal product prepared in a pharmacy following a prescription for an individual patient") from the 'officinal formula' ("any medicinal product which is prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia that is intended to be supplied directly to the patients served by the pharmacy"). 171 Broadly speaking, compounded drugs are not as closely monitored as industrial products and do not follow good manufacturing practices, and are therefore not approved by Regulatory Agencies; however, as they fill a "niche" and can potentially allow or improve treatment in well-defined populations, pharmacy preparations can be used in selected settings. 171 Indeed, caution when using these drugs is necessary, as the use of pharmacy preparations has been associated to some of the risks reported for counterfeit medications, such as the presence of contaminants: in 2012, an outbreak of meningitis, with 64 deaths and 689 nonfatal complications 172 occurred following Aspergillus fumigatus contamination of methylprednisolone vials produced by the New England Compounding Center (NECC). 173 Likewise, compounded drugs might contain wrong dosages of the intended drug, possibly resulting in unreliable clinical effects. Despite these similarities, it is clear that counterfeit medications and compounded drugs are different products, with the former being produced by generally untrained individuals with no concerns for the users' health and the latter being instead carefully manufactured by trained professionals in order to address an unmet need.

The use of counterfeit medication has several costs for society and public health, 127 from the damage to intellectual property to the already reported harmful effects to the consumer.

Damage to intellectual property − similarly to what occurring for software piracy or counterfeiting of non-medical products, such as toys, apparel or luxury goods − has hidden costs which are rarely clearly evident to the consumer, 127 such as the loss of revenue for the producer, the reduced availability of funds for research and development (R&D), and often loss of jobs for affected companies − "When Banks Fail, It Is Seldom Bankers Who Starve." 174 While this is true for all societies targeted by counterfeiters, it becomes of paramount importance for medical companies, which spend large part of their revenue on R&D 127 and wouldn't find it profitable to engage in further research projects only to have them "stolen" by counterfeiters. As investments in R&D could be used to reduce prices of current products or to develop new drugs, a vicious cycle might develop in which request for cheaper, counterfeited products actually prevents companies from providing cheaper, effective products.

Harmful effects on consumers, on the other hand, might be more evident to the general population. First and foremost, money spent on a nonworking treatment is effectively lost, result in a direct economic damage to the user; the same would apply for unsuccessful transactions in which despite the payment, no product is received by the buyer. 127 The risks of unsupervised use of counterfeit drugs have already been described; additionally, use of tablets devoid of any active ingredients can have potentially serious consequences, as in the absence of any treatment, the underlying condition might progress, leading to worse clinical outcomes for the unaware user. On top of that, the public health costs of undesired effect of contaminants − whether microbial, chemical, or APIs − should also be considered: as occurred with the glibenclamide contamination, 143 use of counterfeited medication might also have potentially fatal consequences. 144 Liver damage, ischemic stroke, and kidney failure have been reported following accidental intake of toxic compounds or undeclared APIs: management of these conditions further weighs on public health.

Based on current evidence, it can be assumed that the counterfeit market is flourishing because of an ever-increasing demand, largely supported by the lacking awareness of the health risks and sub-standard efficacy of these products. 133 As a consequence, strategies acting to reduce demand, mostly by raising awareness of the potential issues, could be a useful weapon in the fight against counterfeiters. Education thus becomes the most reliable way to prevent the spread of the counterfeit phenomenon, and physicians should always suggest their patients not to buy medications online. 117 Public education, however, is a daunting and complex challenge for public health, requiring the involvement of international authorities and the development of a shared policy to fight the counterfeit phenomenon. Indeed, in 2006, the WHO has launched the International Medical Products Anti-Counterfeiting Taskforce (IMPACT), a network of experts aiming to halt the production and marketing of counterfeited medical products, 6 and likewise educational campaigns have been promoted in the United States 137 and in Europe. 175 The relevance of such multifaceted approaches has recently been rekindled by the illegal marketing of counterfeit COVID-19 vaccines, 176 highlighting the general disregard counterfeiters have for the health of patients. The EMA and the European Directorate for the Quality of Medicines (EDQM) are in first line in facing counterfeits and in studying strategies to reduce the epidemy of falsified medicinal products. Henceforth, the Council of Europe is currently supporting an international convention dealing with the criminal law field on counterfeiting of medical products and similar crimes involving threats to public health. 177 The States Parties must criminalize: (i) the manufacturing of counterfeit medical products; (ii) supplying, offering to supply and trafficking in counterfeit medical products; (iii) the falsification of documents; (iv) the unauthorized manufacturing or supplying of medicinal products and the placing on the market of medical devices which do not comply with conformity requirements. The chart of signatures and ratifications shows that, as of April 20, 2021, some Members did not sign nor ratify the document yet (Andorra, Azerbaijan, Bulgaria, Czech Republic, Estonia, Georgia, Greece, Ireland, Latvia, Malta, Monaco, Montenegro, Netherlands, North Macedonia, Norway, Poland, Romania, Slovak Republic, Sweden, and United Kingdom), but the largest European States did, as well others not members of the Council, such as Belarus, Benin, Burkina Faso, Côte d'Ivoire, Guinea, Israel, Marocco, and Niger. 178 These regional differences suggest that this strategy is not universally perceived as convenient or effective in facing counterfeits.

The FDA currently sponsors a public campaign named "BeSafeRx", characterized by a specific warning to beware of online pharmacies that: (i) allow to buy drugs without a prescription from the doctor; (ii) offer deep discounts or cheap prices that seem "too good to be true"; (iii) send spam or unsolicited email offering cheap drugs; (iv) are located outside of the United States. 179 No data have been published yet on the efficacy of the campaign, but it is to be noted that this strategy addresses only indirectly the issue of the counterfeit drugs.

The Fakeshare is a European project coordinated by the Italian Medicines Agency (AIFA), launched in 2013 and aiming to produce public awareness on the pandemic use of counterfeit medicines in the continent. The project produced a public advertisement translated in the European languages showing the risks of these products, such as a picture of a male (not by chance) mouth with a gun bullet on the tongue ready to swallow illustrating the message "Buying Medicine online: Think you know what you are getting?". 180 Although meritorious, the output and the social redemption of this campaign are not known.

Machine Learning, which has been used with some successes to combat digital opioid access, 181 has also been considered among the possible strategies to face the increasing use of social networks, like Facebook, Instagram, and Twitter, 2,113 to spread and sell illegal and counterfeit drugs. However, this solution has not been adopted yet to detect, classify, and report illicit online marketing and sales of drugs for sexual medicine.

Additionally, the enactment of telemedicine during COVID-19 has proven that remote consultations are an attractive approach for sexual health, as for many other branches of clinical medicine. 182, 183 While clinical assessment cannot be fully performed with a video interview, there is no doubt that a remote consultation would be far more beneficial than "asking doctor Google". 184, 185 Telemedicine might also be beneficial in the fight against counterfeit medications: the availability of quick, anonymous and possibly cheap remote consultations issued by certified specialists might encourage patients to refrain from self-diagnosis and self-treatment. However, no definite evidence exists at this time of the efficacy of this strategy.

While social interventions are fundamental to contrast counterfeit drugs, technical solutions may also be crucial and could be helpful to overcome the potential gaps ( Figure 3) . While, as a rule of thumb, it would be wise to refrain from buying drugs online at all, it is not uncommon for people to get PDE5i from peers such as friends and colleagues, 136 with little information, if any, on the source of the drug. Several studies performed in the last years have collected the telltale signs of a counterfeit medication: drugs shipped or sold without accompanying leaflets or outer packaging, missing a clear expiration date or information on manufacturing country 19,65 are most likely not genuine products. Since pills and tablets are the most likely products to be counterfeited and their form allows for easy storage (once again, increasing the risks of microbial contamination), the product's shape, color and aspect can be selected or modified by the manufacturer to increase similarity to the genuine product. Therefore, several strategies have also been envisioned by pharmaceutical companies to identify a counterfeit product by the external packaging only, including the use of serial numbers, barcodes, holography, radiofrequency identification device, or unreplaceable sealings on the package itself. 119 While theoretically able to solve the issue of counterfeit medications, such strategies are not always applicable: as an example, the costs for the radiofrequency identification device method are often excessively high, reaching up to billion dollars for large-chain pharmacies, 6, 186 and serialization requires several checks by manufacturers, importers, distributors and resellers, with some countries unable to meet the deadline proposed by regulatory agencies. Of course, this is on top of other concerns, such as the issue of patients' privacy and data security. 7 This once again highlights the need of a more comprehensive approach, supported by larger authorities, such as FDA and WHO.

From a technical point of view, different analyses on samples are available to researchers having access to a modern laboratory 134 : several techniques have been successfully used in the last decades to perform assessment of any tablet's contents (Table 1) . While some chromatography techniques require destruction of the tablet itself, possibly becoming a problem from a legal point of view, 14, 68 nondestructive techniques, such as near-infrared spectroscopy, 14 Raman spectroscopy 12 or nuclear magnetic resonance relaxometry, 48, 132 could be helpful in these regards by leaving the tablet intact. Available techniques also differ for sensitivity, costs, required training and personnel, limiting the possible applications in different settings: therefore, relying upon technical investigations alone in order to identify all counterfeit medications being shipped worldwide is not a feasible strategy.

Last, but not least, among the possible pharmaceutical forms of the PDE5i, the orodispersible one seems particularly interesting for its pharmacokinetic characteristics. 187 In particular, the sildenafil orodispersible film (SODF), based on hydrophilic polymers with drug and other excipients, expresses the unique and peculiar ability to preserve the male intimacy through a convenient and discrete dosage form. 188 Differently from the other pharmaceutical formulations of the products belonging from the same class of drugs, being not easily recognized as a drug, the Desorption electrospray ionization (DESI) mass spectrometry 93 Differential scanning calorimetry (DSC) 19 Dissolution test 36, 91 Dynamic thermal analysis 78 Fourier-transform infrared spectroscopy (FTIR) 14, 19 Gas chromatography−mass spectrometry (GC-MS) 23 HPLC -charged aerosol detector (HPLC-CAD) 84 High-performance thin layer chromatography (HP-TLC) 83 Hyperspectral imaging techniques 96 Infrared spectroscopy (IR) 14, 18, 25, 55, 90 Instrumental neutron activation analysis (INAA) 41, 42 Ion beam analysis (IBA) 42 Laser desorption/Ionization 89 Liquid chromatography (LC) 89 LC -quadrupole-time of flight mass spectrometry (LC-QTOF-MS) 82 LC -quadrupole-time of flight tandem mass spectrometry (LC-QTOF-MS/MS) 38,79−82 LC -charged aerosol detector (LC-CAD) 75 LC -diode array detector (LC-DAD) 75 LC -diode array detector and mass spectrometry (LC-DAD-MS) 49 LC -diode array detector and tandem mass spectrometry (LC-DAD-MS/MS) 50 LC -mass spectrometry (LC-MS) 18 Multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) 52 Near infrared (NIR) spectroscopy 14,35,36,49−51 Nuclear magnetic resonance (RMN) relaxometry 48 Nuclear magnetic resonance (RMN) spectroscopy 13,26,33,37−40 Paper spray ionization (PSI) − Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) 105 Physical profiling 25, 103 Raman spectroscopy 12 Tandem mass spectrometry (MS/MS) 24 Thermo-gravimetry (TG) 19 (continued) Strategies Against Counterfeit PDE5 Inhibitors SODF could be classified as an "intimacy-sparing" PDE5i. Moreover, SODF does not require the intake of a liquid, hence reducing the anxiety of the patient and the stigma of assuming a well recognizable drug to address ED, while the large surface area leads to rapid disintegration in the mouth. 188 A very interesting add on is the fact that the SODF appear as the unique PDE5i virtually exempt from the risk of counterfeiting. 189, 190 On top of the still valid patents for ODF, 191, 192 production of such formulations require, in fact, several expensive steps needing highly specialized laboratories and materials 131 (ie, IBSA ODF): as an example, the hygroscopic nature of the support and of the drug require special precautions during production, and excessively long exposure before individual packaging could damage the quality and efficacy of the drug. 189 In fact, the performance of SODF is dependent on manufacturing processes that maximize the porous structure of the tablet matrix, incorporating a disintegrating agent, and the use of highly water-soluble excipients to allow quick ingress of water, finally facilitating rapid oral disintegration 193 ; all technical aspects which are tremendously hard to be replicated in the black-market setting. Therefore, on top of the already demonstrated safety and efficacy, 187,194−196 the reliability and reduced risk of counterfeiting are additional added benefits of the SODF formulation.

In this review, we systematically reviewed currently available literature concerning the use of counterfeit PDE5i, highlighting several topics relevant for sexual medicine experts as well as for the general population. To our best knowledge, this is the first time that this topic has been addressed systematically, highlighting all known risks for individual and public health as well as pointing out available strategies aimed to contain the counterfeit phenomenon, and reasons for their partial success. The present paper, however, has some limitations, mostly inherent to the available literature being investigated − such as the lack of any clear rate of counterfeit medication use and the presence of a limited amount of clinical studies.

While generally under-reported, counterfeit medications are a tangible issue requiring intervention, due to the potential risks for healthcare. This becomes of paramount importance in the context of sexual medicine, being pro-erectile drugs the most counterfeited products in several countries. As reported in different guidelines, 117,138−142 PDE5i are safe and effective if appropriately used; however, several risks and complications might arise following use of counterfeit medications. Microbial contamination, inadequate dosing of the active pharmaceutical ingredients and adulteration with other drugs or toxic compounds can both have direct effects on the consumers' health; additionally, unsupervised use results in decreased awareness of the underlying risk factors, increasing the potential burden for healthcare. Such costs should also consider the reduced reinvestments on R&D by medical companies, as well as the potential costs for public health from inadequate treatment and side effects of contaminants. While technologies to detect counterfeit are increasingly available, political aspects and the costs and required expertise limit their application. Within the various pharmaceutical formulations, the ODF is the less likely to be prone to be counterfeited and warrants a unique originality of its content, dosage, and safety. Physicians treating sexual dysfunctions and pharmacists should inform their patients and clients about the issues of counterfeit medical products, as well as suggest refraining from buying drugs online and taking tablets of dubious origin from peers.

Corresponding Author: Emmanuele A. Jannini, MD, Chair of Endocrinology and Medical Sexology (ENDOSEX), Ultra-performance liquid chromatography -high resolution tandem mass spectrometry (U-HPLC-HRMS/MS) 29, 30 Ultra-performance liquid chromatography -mass spectrometry (U-HPLC-MS) 22 Ultra-performance liquid chromatography -ultra violet detection (UHPLC-UV) 16 Ultra-performance liquid chromatography hybrid-ion trap-Orbitrap mass spectrometry (UHPLC-Orbitrap-MS/MS) Department of Systems Medicine, University of Rome Tor Ver-

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