In September 1998, Pfizer received European marketing authorization (MA) for Viagra, a medication containing sildenafil as its active pharmaceutical ingredient (API). This drug was approved for the treatment of erectile dysfunction [1]. Since its launch, Viagra has frequently been counterfeited. Starting in the early 2000s, a significant number of samples were analyzed at the RIVM, specifically at the Center for the Quality of Chemical-Pharmaceutical Products (RIVM-KCF) in collaboration with the Laboratory of Analytical Chemistry (RIVM-LAC).

Following Viagra, Lilly introduced Cialis® in November 2002, and Bayer launched Levitra® in March 2003 [1]. These medications serve a similar purpose as Viagra, with their respective active ingredients being tadalafil (Cialis®) and vardenafil (Levitra®). Given the likelihood of counterfeiting, analytical methods were adapted to assess both the qualitative and quantitative composition of vardenafil and tadalafil.

The analyzed samples were examined to determine the presence of sildenafil or related substances, as well as to compare them with authentic products and previously analyzed samples. These included fake Viagra tablets with or without sildenafil, tablets that differed in color and shape but contained sildenafil, as well as capsules, gels, beverages, and herbal products claiming to contain sildenafil. Some herbal products were found to contain new compounds structurally similar to sildenafil but lacking toxicological data. By the end of 2004, counterfeit versions of Cialis® had also been submitted for testing.

Samples were classified into five main categories: Original, Counterfeit, Imitation, Analog, and Other. Original tablets were identical to the genuine product. Counterfeit tablets mimicked the original medication in shape, color, and branding. Imitations, while not visually resembling the authentic drug, suggested similar pharmacological effects. Any non-tablet dosage forms, such as capsules, gels, or drinks, were categorized as Imitation. Products containing newly identified sildenafil analogs were classified under Analog due to their comparable risk profiles. Samples that lacked sufficient data for classification were placed in the Other category.

The Counterfeit and Imitation categories were further divided into five subcategories based on health risks associated with the presence and dosage of the correct API (sildenafil or tadalafil).

For all samples analyzed between 2000 and 2004, key aspects such as appearance, qualitative and quantitative data, near-infrared (NIR) correlation, and classification were recorded (see Appendix 3). Most samples were tested for sildenafil or other APIs, and while sildenafil was frequently detected, it was often present in lower amounts than declared. Additional APIs found included amphetamine, clomiphene, chloramphenicol, dipyrone, fluoxetine, tadalafil, yohimbine, gamma-aminobutyric acid (GABA), caffeine, L-arginine, indigotine, and quinine. Some samples contained combinations of these APIs, with or without sildenafil.

In addition to registered APIs, herbal products have been found to contain unknown sildenafil analogs such as homosildenafil, hydroxyhomosildenafil, and acetildenafil [5]. These compounds were identified in samples analyzed by authorities in the United States, Canada, Singapore, South Korea, and Japan [6-9] around the same time. Below are the chemical structures of sildenafil, tadalafil, vardenafil, and their analogs. Notably, none of the analyzed samples contained vardenafil.

Sample 6398A appeared to consist solely of Viagra tablets, while sample 6398B contained tablets that combined Viagra with clomiphene (see Appendix 3).

Health risks associated with these products often stem from their pharmacological composition. Counterfeit drugs pose dangers when they contain different amounts of Viagra or tadalafil compared to authentic versions of Viagra or Cialis®. If the quantity is lower than expected, the pharmacological risk is usually minimal. However, higher-than-declared amounts can significantly increase potential health hazards. Only a few analyzed samples were found to have excessive levels of active ingredients.

The risks escalate further when counterfeit drugs contain APIs other than Viagra or tadalafil. If the product contains only caffeine, the risk is relatively low. However, the presence of substances like amphetamine, chloramphenicol, or dipyrone can lead to severe pharmacological effects or side effects, depending on the dosage (see Appendix 1).

An even greater concern arises when counterfeits include multiple APIs. Unexpected drug interactions can occur between two or more active ingredients. To obtain marketing authorization (MA) for a multi-ingredient product, studies must be conducted to assess potential interactions. The absence of such studies presents an additional risk—even for seemingly harmless combinations like Viagra and caffeine.

A particularly high public health risk comes from counterfeit products containing structurally similar compounds to known APIs. These substances may have pharmacological activity but have not been approved for use, and there is little to no scientific data on their safety and effectiveness.

The dosage form of a product can also impact consumer perception and risk. While tablets are easily recognized as pharmaceuticals, a canned beverage may not immediately appear medicinal, leading to unintentional consumption.

In addition to their chemical composition, counterfeit and imitation drugs can pose risks due to inaccurate, missing, or misleading information on packaging, labels, or patient leaflets. This aspect was not the primary focus of the study, but significant variation was observed in packaging among received samples. Some arrived in complete packaging, including boxes, leaflets, blister packs, and labeled dosage forms, while others were simply enclosed in plastic bags or blister packs without any identifying information. It remains unclear how these products are presented to consumers, making it difficult to assess the full extent of this risk.

Serious public health dangers arise when counterfeit drugs contain incorrect information regarding composition, dosage, side effects, or contraindications. Such inaccuracies can mislead users, increasing their exposure to potential medical emergencies. In urgent situations, misleading product details may hinder appropriate medical treatment.

Additionally, neither Viagra nor tadalafil should be used by individuals with heart failure, even if their condition is undiagnosed. These drugs must also not be combined with organic nitrate-containing products, such as "poppers," which are commonly used recreationally. The risk is even greater when a product is marketed as "natural" but secretly contains an active pharmaceutical ingredient. In such cases, users may not associate adverse effects with the product, assuming that natural remedies are inherently safe. (https://doganaccia2000.it)