Analysis of registration and production of vitamin K antagonists in the EAEU member states

Introduction

The history of the discovery of vitamin K antagonists is linked to the investigation of hemorrhagic diathesis observed in cattle in North America at the beginning of the 20th century. In the 1920s, studies emerged explaining this disease as a deficiency of prothrombin in the blood [1], occurring when cows consumed hay made from spoiled sweet clover [2]. Research results showed that the cause of fatal bleeding in animals was a deficiency of prothrombin complex factors, and the toxic substance isolated from spoiled sweet clover was characterized as 4-hydroxycoumarin and named "dicumarol" [3, 4].

Vitamin K antagonists are used in clinical practice for the treatment and prevention of thrombosis and embolism of blood vessels: acute and recurrent venous thrombosis, pulmonary embolism; in secondary prevention of myocardial infarction, prevention of thromboembolic complications in patients with atrial fibrillation, heart valve lesions, or prosthetic heart valves; and in the prevention of postoperative thrombosis [5].

Based on their chemical structure, vitamin K antagonists are classified into groups of monocoumarins (warfarin, phenprocoumon), dicoumarins (dicumarol), and indandiones (phenindione, diphenadione). Warfarin is considered the safest representative of vitamin K antagonists, their "gold standard." In Russia, experience with warfarin is limited compared to other antithrombotic agents (e.g., direct oral anticoagulants).

Disadvantages of vitamin K antagonists include difficulties in controlling their anticoagulant effect due to an excessively long (phenprocoumon) or excessively short (ethyl biscoumacetate) half-life, and incomplete absorption in the gastrointestinal tract (dicumarol). Phenindione and diphenadione possess anticoagulant effects similar to coumarins, but according to Perkins J. [7], they should not be first-line drugs due to the high frequency of adverse effects they cause (various skin manifestations and toxic effects on the liver). An exception is patients who have had allergic reactions to coumarin derivatives. Additionally, phenindione metabolites can cause pink or orange discoloration of urine, misleading patients and physicians regarding possible hematuria [8]. In 2016, Indian researchers confirmed the effectiveness of a monocoumarin group derivative, acenocoumarol, in atrial fibrillation, heart valve replacement, secondary prevention of myocardial infarction, treatment of deep vein thrombosis, and after surgical operations, and recommended acenocoumarol for use in India [9].

The effectiveness of the vitamin K antagonist group is well-proven in the treatment and prevention of thrombosis and thromboembolism; however, in many guidelines, the term "vitamin K antagonists" refers only to warfarin preparations in various dosages [6, 10]. For nearly 80 years, warfarin was the mainstay of anticoagulant therapy [10], but in recent years, direct oral anticoagulants (DOACs) have become the anticoagulants of choice.

Vitamin K antagonists have the following drawbacks: a narrow therapeutic window, a somewhat unpredictable anticoagulant effect, the need to assess the international normalized ratio (INR) to select the maintenance dose, careful laboratory monitoring during therapy, and significant individual response variation to the drugs due to genetic factors [11].

Thus, the new group of DOACs demonstrates efficacy comparable to warfarin, while offering ease of use due to fixed doses and the absence of a need for routine coagulation monitoring (determination of prothrombin time and INR). Furthermore, DOACs generally show a lower rate of intracranial bleeding than warfarin, which is a critical advantage, given that intracranial hemorrhage is the most dangerous complication of anticoagulant therapy [12].

Objective

To study the structure and development trends of the pharmaceutical market for vitamin K antagonists in the member states of the Eurasian Economic Union (Russia, the Republic of Belarus, the Republic of Kazakhstan, the Republic of Armenia, and the Kyrgyz Republic) regarding the rates of state registration of medicinal products and the localization of production of active pharmaceutical ingredients (APIs) and finished dosage forms (FDFs).

Materials and methods

A search for drug marketing authorizations was conducted in the state registries of the Russian Federation, the Republic of Belarus, the Republic of Kazakhstan, the Republic of Armenia, and the Kyrgyz Republic. A database on the processes of state registration and production of vitamin K antagonists was developed in Microsoft Excel. Data on drugs approved in Russia were obtained from the State Register of Medicines (GRLS) from 2006 to 2025. Information on approved drugs in other EAEU member states was collected from their respective state registries for the year 2025. The study employed methods of content analysis, critical analysis, and classification.

Results and discussion

According to the ATC classification, the group of vitamin K antagonists includes the following 10 active substance names: warfarin, acenocoumarol, dicumarol, diphenadione, clorindione, tioclomarol, phenindione, phenprocoumon, fluindione, and ethyl biscoumacetate [13]. Information on the available range of vitamin K antagonists in Russia is presented in Table 1.

Table 1. Vitamin K antagonists approved for medical use in the Russian Federation (2025)

Medicinal products of the following INNs: 1) dicumarol, 2) phenprocoumon, 3) ethyl biscoumacetate, 4) clorindione, 5) diphenadione, 6) tioclomarol, and 7) fluindione have not undergone state registration in Russia or the EAEU.

Currently, 2 INNs of vitamin K antagonists are available in Russia — acenocoumarol and warfarin, represented by 5 trade names (4 warfarin TNs and 1 acenocoumarol TN). The drugs are registered in the tablet pharmaceutical form at the following dosages: 2.5 mg for warfarin preparations and 2 mg for the acenocoumarol preparation.

Fig. 1 shows a diagram reflecting the registration rates of vitamin K antagonists in Russia from 2006 to 2025.

Fig. 1. Dynamics of registration of vitamin K antagonists in Russia (ATC code: B01AA)

The first registry entry for a issued marketing authorization for a vitamin K antagonist dates back to 01.12.2006 — the medicinal product "Marevan" (MA Holder: Orion Corporation Orion Pharma, Finland). From 2006 to 2010, the range of vitamin K antagonists increased, with an average annual growth of 1.4 approved drugs. The largest number of trade names in Russia was recorded in the period from 2010 to 2016 — 8 trade names. From 2010 to 2023, the number of INNs available in Russia was 3 — warfarin, acenocoumarol, and phenindione, but since 06.2023, the registration of the phenindione preparation has been terminated. Since 2017, a negative trend in the registration of vitamin K antagonist drugs has been observed in Russia, and today 5 trade names are available. State registration has been canceled for warfarin in 3 mg and 5 mg dosages; currently, warfarin tablets are available in a single dosage — 2.5 mg.

Figs. 2-3 show diagrams reflecting the localization of production of APIs and FDFs for vitamin K antagonists registered in Russia as of 2025.

Fig. 2. Analysis of the localization of synthesis of active pharmaceutical substances of vitamin K antagonists

The synthesis of the active pharmaceutical ingredient warfarin is localized in India, China, Sweden, and the Czech Republic. The API for acenocoumarol is synthesized in Hungary. The synthesis of APIs for vitamin K antagonists is not localized on the territory of Russia.

Fig. 3. Analysis of localization of production of finished dosage forms of vitamin K antagonists

The production of finished dosage forms for every second vitamin K antagonist drug is localized in Russia. To gather information on the production of finished dosage forms, the production stages "All stages, including final quality control" and "Manufacturer (of finished FDF)" specified in Section 6 of the marketing authorizations were considered [5].

Fig. 4 presents summary data on the number of trade names of warfarin drugs in the EAEU member states as of 07.2025. Warfarin preparations were chosen as the object of study because they are used in every member state. Acenocoumarol preparations are registered only in Russia, and phenindione preparations — since 06.2023 — only in the Republic of Belarus.

Fig. 4. The proportion of trade names of warfarin drugs registered in the EAEU countries

When creating the diagram, information from the state registers of the EAEU member states was used [5, 16-19]. The count of trade names was performed for each EAEU member state, regardless of whether the trade name was registered in the Russian Federation or another state.

The largest number of warfarin trade names is registered in Russia — 5 names, in the Republic of Kazakhstan — 4 names, in the Republic of Belarus, the Republic of Armenia, and the Kyrgyz Republic — 3 trade names of warfarin each. The available assortment in the EAEU member states is comparable. The widest choice of warfarin dosages is available in the Republics of Kazakhstan, Belarus, and Armenia — 5 mg, 3 mg, 2.5 mg. In Kyrgyzstan and Russia, warfarin is available only in the 2.5 mg dosage.

Conclusion

Out of 10 INNs of vitamin K antagonists, 3 names are approved in the EAEU territory — warfarin, acenocoumarol, and phenindione. Based on literature data, it is known that relatively widespread medical use persists only for warfarin preparations. Acenocoumarol is approved for medical use in the EAEU only in Russia, and phenindione — only in the Republic of Belarus. Clinical studies of acenocoumarol are known to have been conducted in India.

The current trend in the pharmaceutical market of vitamin K antagonists in Russia is a reduction in the assortment — from 2017 to 2025, the number of trade names of vitamin K antagonists decreased from 8 to 5 names; in 06.2023, the state registration of the only phenindione drug in Russia (Phenylin) was canceled.

The trend towards a shrinking assortment can be explained by the difficulty of selecting a therapeutic dose, the need for careful laboratory monitoring of therapy outcomes, and the emergence on the pharmaceutical market of anticoagulants with fixed doses (the DOAC group). In many studies, the safety of warfarin and DOACs is stated as comparable; however, researchers note the difficulty of selecting warfarin doses.

The production of warfarin API is not localized in Russia. The production of finished dosage forms for every second warfarin drug registered in the Russian Federation is localized in Russia.

Among the EAEU member states, the production of warfarin API is present only in the Republic of Belarus (RUE "Belmedpreparaty").