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ORIGINAL ARTICLE

Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine

VICTORY Project: a Study of Counterfeit PDE5 Inhibitor (Sildenafil) in Indonesia

Akmal Taher1, Arini Setiawati2

1 Department of Urology, Faculty of Medicine, Universitas Indonesia - Cipto Mangunkusumo Hospital, Jakarta, Indonesia.2 Clinical Study Unit, Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.

Correspondence mail:Clinical Study Unit, Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia. Jl. Salemba 6, Jakarta 10430, Indonesia. email: arinisetiawati@yahoo.com.

ABSTRAKTujuan: untuk mengkuantifikasi banyaknya sildenafil palsu di Indonesia. Metode: penelitian ini dilakukan

di 4 area besar: Jakarta, Bandung, Jawa Timur (Surabaya dan Malang), serta Medan. Tablet sildenafil 100 mg dibeli dari apotek, toko obat, penjual obat jalanan dan 3 situs web di Indonesia. Tempat penjualan dipilih secara acak (random sampling) dari setiap jenis tempat penjualan. Tablet sildenafil yang dibeli dikirim ke Divisi Operasi Kualitas Pfizer di Dalian, Cina untuk dinilai keasliannya (dengan analisis spektrum infra merah). Semua tablet yang palsu kemudian dikirim ke laboratorium obat palsu Pfizer di Sandwich, Inggris, sebagian dianalisis secara kuantitatif kadar sildenafil dalam setiap tablet (dengan HPLC). Hasil: sejumlah 518 tablet sildenafil 100 mg dibeli dan dikirim ke Dalian. Dari jumlah ini, 284 tablet (55%) adalah sildenafil asli dan 234 tablet (45%) adalah sildenafil palsu. Sildenafil palsu paling banyak ditemukan pada pedagang obat jalanan (100%), toko obat (56%), dan dari internet (33%), tetapi di apotek juga ada sildenafil palsu (13%). Kandungan sildenafil dari 106 tablet palsu yang dianalisis bervariasi antara 24 sampai 157 mg per 100 mg tablet. Tidak dilakukan analisis untuk menentukan zat aktif lain. Kesimpulan: sebanyak 45% tablet sildenafil 100 mg di Indonesia ditemukan palsu dan terdistribusi luas di penjual obat jalanan, toko obat, dan apotik. Laporan ini ditujukan kepada para calon konsumen, para profesional di bidang kesehatan dan pembuat kebijakan agar mewaspadai masalah ini.

Key words: sildenafil, farmasi, toko obat, penjual obat jalanan.

ABSTRACTAim: to quantify the extent of counterfeit sildenafil in Indonesia. Methods: the study was conducted in 4

big areas: Jakarta, Bandung, East Java (Surabaya and Malang), and Medan. Sildenafil 100 mg tablets were purchased from pharmacies, drugstores, street peddlers, and 3 Indonesian websites. The outlets were chosen by random sampling in each stratum (type of outlet). Sildenafil tablets purchased were sent to Pfizer Quality Operations Division, Dalian, China, for authenticity evaluations (by infra red spectral analysis). All counterfeit tablets were then sent to Pfizer Counterfeit Medicines Laboratory, Sandwich, UK, a portion of which were analyzed quantitatively for sildenafil concentration per tablet (by HPLC). Results: a total of 518 sildenafil 100 mg tablets were collected and sent to Dalian. Of these tablets, 284 tablets (55%) were genuine sildenafil and 234 tablets (45%) were counterfeit sildenafil. Counterfeit sildenafil were mostly found in street peddlers (100%), in drugstores (56%), and from internet (33%), but pharmacies also had (13%) counterfeit sildenafil. The sildenafil content of 106 counterfeit tablets analyzed varied from 24 to 157 mg per 100 mg tablet. No analysis was done to determine other active ingredient. Conclusion: 45% sildenafil 100 mg tablets in Indonesia were

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INTRODUCTIONViagra®, the innovator of sildenafil, is a

breakthrough drug in terms of its ability in oral form to help men with erectile dysfunction (ED) to obtain or maintain an erection for satisfactory sexual relations. In United States, more than 18 million men above the age of 20 years have erectile dysfunction.1

Counterfeit drugs, according to the World Health Organization (WHO), are those that deliberately and fraudulently mislabelled with respect to identity or source: their quality is unpredictable as they may contain the wrong amount of active ingredients, wrong ingredients or no active ingredients. They are manufactured in clandestine laboratories with no possibility of control.2

Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, is an effective oral medication for ED. Other drugs of the same class with the same indication are vardenafil (Levitra®) and tadalafil (Cialis®). These drugs are prime targets for counterfeiting because of their high price and the embarrassment associated with the underlying condition. In fact, PDE5 inhibitors were the most commonly counterfeited class of product in Europe.3 Until now, sildenafil is the most commonly counterfeited drug all over the world because it is the most famous drug as the first oral anti ED. During 5 years from 2004 to 2008, 35.8 million counterfeit sildenafil tablets were seized in Europe. In 2004, law officers seized 10.6 million counterfeit sildenafil tablets, which were seven times the number of all other counterfeited Pfizer products combined.4

It was estimated that 0.6-2.5 million men in Europe could be exposed to illicit sildenafil. For comparison, IMS Health estimated the number of users of legal sildenafil in the European Union were 2.5 million in 2006.4

We do not have this kind of data in Indonesia. Pfizer Inc., New York, USA, initiated a market research to quantify the extent of counterfeit

sildenafil in Indonesia and assigned PT Integrity Indonesia and PT. PharmaCare Marketing Services Indonesia to conduct the study, which was called “Victory Project”. The objective of this study was to quantify the extent of counterfeit sildenafil in Indonesia, and to alert the potential consumers, health professionals and regulators about this problem.

METhODSThe study was conducted in four big

areas: JaBoDeTaBek (Jakarta, Bogor, Depok, Tangerang and Bekasi), Bandung, East Java (Surabaya and Malang), and Medan. Sildenafil 100 mg tablets were purchased from all types of outlets: pharmacies (ordinary, chain, and hospital), drugstores, street peddlers, and 3 different Indonesian websites. The outlets were chosen by random sampling in each stratum (pharmacies, drugstores, and street peddlers).

Sildenafil 100 mg tablets purchased were sent to Pfizer Quality Operations Division, Dalian, China, for authenticity evaluations of the sildenafil tablets. The evaluation was performed qualitatively by infra red (IR) spectral analysis. The counterfeit tablets were separated into 6 different formulations based on the IR analyses. All counterfeit tablets found were then sent to Pfizer Counterfeit Medicines Laboratory, Sandwich, UK, a portion of which were analyzed quantitatively for sildenafil content per tablet (by HPLC), and determination of its purity (% impurity).

RESULTSFrom the 4 big areas, 86 pharmacies, 38

drugstores, and 30 street peddlers were chosen. From these outlets and 3 websites, a total of 518 sildenafil 100 mg tablets were purchased and sent to Dalian. Among these tablets, 284 tablets (55%) were authentic sildenafil and 234 tablets (45%) were counterfeit sildenafil.

found counterfeit and widely distributed in street peddlers, drugstores, and pharmacies. This report is aimed to alert the potential consumers, health professionals and regulators of this problem.

Key words: sildenafil, pharmacy, drug store, street peddler.

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The authentic and counterfeit sildenafil tablets are shown in each area (Figure 1) and in each group of outlets (Figure 2).

Counterfeit sildenafil tablets were mostly found in JaBoDeTaBek (165 tablets=50%), followed by East Java (55 tablets=50%).

Counterfeit sildenafil tablets were mostly found in “illegal” outlets, especially in street peddlers (100%), and in drugstores (56%). Pharmacies also had 13% counterfeit sildenafil. Among 12 sildenafil tablets purchased from the internet, 4 were counterfeit.

The outlets with counterfeit tablets and the counterfeit tablets in each type of outlet can be seen in Table 1.

Among 234 counterfeit sildenafil tablets, 53% contained dehydrated calcium sulphate, 32% maltose dextrin, 5% lactose, 4% microcrystalline cellulose, 4% avicel PH 102 (a type of cellulose), and 2% unknown. Based on Dalian’s IR analysis, the similarity to authentic sildenafil varied from 13 to 69%.

The packaging of counterfeit sildenafil: 73% were in blister, with its box and package

insert, which were very similar to the original packaging, 11% in bottle, and 16% were loose tablets (might be taken from the bottle).

Pfizer Sandwich took 1 to 2 counterfeit tablets from each outlet with counterfeit tablets to be analyzed for sildenafil content (Table 1). A total of 106 tablets were analyzed and sildenafil was found in every counterfeit tablet, ranging from 24 to 157 mg per 100 mg tablet: 64% contained 50 mg or less per tablet, 25.5% between 50 and 95 mg, 4.7% between 95 and 105 mg, and the remaining 5.7% contained more than 105 mg. No analysis was done to determine other active ingredients.

DISCUSSIONIn the present study, some sildenafil were

present in every counterfeit sildenafil tablet (24–157% per 100 mg tablet). Counterfeit sildenafil tablets seized in the United Kingdom contained 40-100% sildenafil per 100 mg tablet5, while in Europe between 2005 and 2009, the sildenafil content in 2383 tablets of suspect counterfeit sildenafil was 0 to >200% of the indicated strength.6 In the Netherlands, among 370 illegally

N = 518

= 50%

= 18%

= 50%

= 20%

Figure 1. The authentic and counterfeit sildenafil tablets in each area

N = 518

= 13%

= 56%

= 100%

= 33%

Figure 2. The authentic and counterfeit sildenafil tablets in each group of outlets

Table 1. The outlets with counterfeit sildenafil tablets

Outlet Total no. of outlets

No. of outlets with counterfeit tablets

Total no. of tablets

No. of counterfeit tablets

No. of counterfeit tablets analyzed for sildenafil content

Pharmacy 86 6 259 34 (13%) 9

Drugstore 38 19 117 66 (56%) 36

Street peddler 30 30 130 130 (100%) 60

Internet 3 1 12 4 (33%) 1

Total 157 56 (36% of total) 518 234 (45% of total) 106

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sold sildenafil tablets collected from 2000 to 2004, only 10 were genuine, sildenafil was often present, but in lower amounts than declared.7

Although the percentage of counterfeit sildenafil found in the present study was alarming (45%), there was no data on other active ingredient that might be present in it and could be hazardous or even fatal. For example, the high content of glibenclamide in counterfeit sildenafil tablets caused severe hypoglycemia in 149 nondiabetic men in Singapore between January 1st and May 26th, 2008. Seven of these men remained comatose as a result of prolonged neuroglycopenia, and four subsequently died.8

Other examples of other active pharmaceuticals in counterfeit sildenafil tablets collected from 2000-2004 in the Netherland were amphetamine, paracetamol, metronidazole, clomiphene, chloramphenicol, dipyrone, fluoxetine, tadalafil, yohimbine, gamma-aminobutyric acid, caffeine, L-arginine, and quinine.7 Even herbal or dietary supplements that were marketed for sexual dysfunction in the US and claimed “100% natural product”, obtained over the counter or directly from the manufacturer using the internet, revealed that some of the tablets analyzed contained an average of 55 mg of sildenafil per capsule.9 In Singapore, among 175 illegal sexual enhancement health products that were claimed to be natural supplements for the enhancement of sexual performance, 134 tablets were found to contain Western drug adulterants, i.e. 123 tablets of these contained sildenafil, 15 tablets contained tadalafil, and 2 tablets adulterated with vardenafil.10

We do not know what other active pharmaceutical ingredients adulterating counterfeit sildenafil tablets were found in Indonesia, so that we are not able to predict the hazardous effects that may arise from these counterfeit sildenafil, not to mention the adverse drug interactions that may occur. Despite the high percentage of counterfeit sildenafil tablets (45%), no adverse events have been reported associated with it. However, this may be due to the poor adverse drug reactions reporting system in Indonesia. Also, because most counterfeit sildenafil tablets were found in illegal drug outlets (drugstores and street peddlers) and

purchased by ED patients without prescription, then the adverse events, if occurred, were never reported. Only if the adverse events were severe or serious, and the subjects were admitted to hospitals, then heathcare professionals (HCPs) acknowledged the adverse events and reported them, if they were obliged to. Since this obligation does not exist, then the adverse events will not be reported and eventually forgotten, as if they never happen.

What are the theoretical hazards of counterfeit sildenafil for ED patients without prescription? It should be noted that counterfeit sildenafil often contains sildenafil, and in this study, it ranged from 23 mg to 157 mg per tablet. First of all, the contraindications of sildenafil use: (i) patients using nitrates, sildenafil will potentiate the hypotensive effect of nitrates causing severe hypotension; (ii) patients with preexisting cardiovascular disease, in whom sexual activity is inadvisable. Then, the warnings and precautions of sildenafil use: (i) age >65 years, hepatic impairment (e.g. cirrhosis), severe renal impairment (ClCr <30 mL/min) will increase plasma levels of sildenafil 40 to 100%; (ii) drug interactions with potent inhibitors of CYP3A4 (ketoconazole, itraconazole, erythromycin, saquinavir) will approximately double the plasma levels of sildenafil, while ritonavir will cause eleven-fold increase; (iii) myocardial infarction, stroke, life-threatening arrhythmias within the last 6 months; hypotension (<90/50 mmHg); hypertension (>170/110 mmHg); cardiac failure or coronary artery disease causing unstable angina.11 High plasma levels of sildenafil may cause optic neuropathy12, priapism11 (painful erections for >6 hours), besides decreased blood pressure until syncope.11 This information, known by the HCPs, but not known by users of sildenafil without prescription may endanger these users. Furthermore, men with ED commonly have comorbid conditions (e.g. hypertension, diabetes) that carry a significant risk for morbidity and mortality. Without a physician visit, these men lose the opportunity to address these underlying conditions.13

In the present study, 5.7% of the counterfeit sildenafil contained more than 105 mg of

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sildenafil (until 157 mg). This high concentration of sildenafil is believed to be the approach of dishonest manufacturers to ensure the efficacy of the products.

From the fact that counterfeit sildenafil were 100% in street peddlers, 56% in drugstores, and 13% in pharmacies, then the potential consumers know where to find most likely the genuine sildenafil.

CONCLUSIONOf the 518 tablets of sildenafil 100 mg

purchased from 4 big areas in Indonesia, 45% were counterfeit. The counterfeit sildenafil tablets were found in street peddlers (100%), drugstores (56%), and in pharmacies (13%), all of which contained sildenafil, ranging from 24 to 157%. No other active ingredients were sought. This report is aimed to alert the potential consumers, health professionals and regulators of this problem.

CONFLICT OF INTERESTThe authors receive study grant from Pfizer

Inc., New York, USA.

ACKNOwLEDgMENTSWe acknowledge Pfizer Inc., New York,

USA for the financial support for this study. We also thank PT Integrity Indonesia for sample collection of sildenafil 100 mg tablets, PT PharmaCare Marketing Services Indonesia for analyzing the data, Pfizer Quality Operations Division in Dalian, China for authenticity evaluations of the sildenafil tablets, and Pfizer Counterfeit Medicines Laboratory in Sandwich, UK for quantitative analysis of sildenafil content in the counterfeit sildenafil tablets.

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