Meldonium – Mildronate Frequently Asked Questions

What is Mildronate?

Mildronate is a registered medicine in different countries available in capsules, solution for injections and tablets dosage form. Its active pharmaceutical ingredient (or active substance) is meldonium which is responsible for pharmacological and therapeutic effects of the drug. Mildronate is a registered trademark of JSC Grindeks.

What is meldonium?

Meldonium (INN – international nonproprietary name) is an active pharmaceutical ingredient (or active substance) of Mildronate. The chemical name for meldonium is trimethylhydrazinium propionate.

What is mechanism of action of meldonium?

Meldonium is a cytoprotective substance, which is used to prevent death of ischemic cells. Its mechanism of actions is based on the regulation of energy metabolism pathways thorough L-carnitine lowering effect. L-carnitine biosynthesis enzymes gamma-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these 2 targets meldonium optimizes cellular energy homeostasis. Free fatty acid inhibition is not a direct pharmacological target of meldonium. However, since L-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of potentially harmful L-carnitine related metabolites, such as long-chain acylcarnitines and trimethyl-N-oxide.

This is important in the treatment of pathologies associated with ischemia (stenocardia, heart failure. stroke), because in these cases the tissues and cells are not getting enough oxygen and nutrients.

What are therapeutic indications of Mildronate?

Mildronate is used for treatment of the following cardiovascular and neurological diseases and disturbances:

Stable angina pectoris, chronic heart failure (NYHA I-III functional class), cardiomyopathy, functional cardiovascular disorders;

Acute and chronic ischemic brain blood circulation disorders;

Reduced working capacity, physical and psycho-emotional overload;

During the recovery period after cerebrovascular disorders, head injury and encephalitis.

Mildronate is included in the guidelines on the management of cardiovascular diseases issued by national societies of cardiology in Latvia.

Where does Mildronate come from?

JSC Grindeks is the major manufacturer of pharmaceutical preparations of meldonium. JSC Grindeks is an international pharmaceutical company with headquarters in Riga, Latvia which manufactures Mildronate in Latvia, Slovakia and Russia.

Why Mildronate (meldonium) is famous with athletes?

Meldonium is a protective drug to guard against heart cells damages during ischemia which can cause infarct and death of athletes because of very high physical exertion. Meldonium does not improve athletic performance, but it can stop tissue damage in case of ischemia. Meldonium got a huge publicity when it turned out that, despite the inclusion in the WADA (World Anti-Doping Agency) list of banned substances for athletes from 1 January 2016, doping tests of many of the world’s leading athletes confirmed presence of meldonium.

In what way (if any) meldonium could enhance performance for an athlete?

There have been no clinical studies providing evidence that acute or chronic use of meldonium increases the athletic performance, and including of meldonium in WADA (World Anti-Doping Agency) Prohibited list has not been justified based on scientific evidence.

How long does meldonium stay in the body after a person has stopped using it?

Although the half-life of meldonium in organism is only 4-6 hours, its complete elimination time from organism is significantly longer.

Because of the non-linerar pharmacocinetics of meldonium, its terminal elimination from the body may last for several months and it depends on a variety of factors such as dose, duration of treatment, individual physiology of the organism, sensitivity of methods and type of samples (blood or urine) used for detection of the substance.

For how long Mildronate should be used?

Depending on the patient’s health condition and disease to be treated, the treatment course of Mildronate may last up to 6 weeks. The treatment course can be repeated twice or thrice a year. Only physicians can follow and evaluate patient health condition and state whether the patient should use Mildronate for a longer period of time or not according to the information provided in the Patient information leaflet and Summary of product characteristics.

Is there long-term data available on people who have taken Mildronate for years?

No, it isn`t. To collect such data JSC Grindeks should perform phase IV study, which is not necessary for medication which has been used for more than 30 years and has proved good safety profile. JSC Grindeks` pharmacovigilance division has been collecting and processing safety data since the beginning of monitoring in 2006.

Why was meldonium banned by WADA (World Anti-Doping Agency)?

There have been no clinical studies providing scientific evidence that acute or chronic use of meldonium increases athletic performance. Inclusion of meldonium in the prohibited list without this kind of evidence cannot be justified. Mildronate’s safety is confirmed by its periodic safety update records and the results of published clinical studies. Based on available data, no adverse reactions related to Mildronate’s use in athletes have been registered so far.

Despite JSC Grindeks’s arguments, evidence and justifications submitted to WADA, it included meldonium in the Prohibited list from 1st January, 2016. In accordance with the results of the extended research, JSC Grindeks has a firm conviction that meldonium should not be included in the Prohibited list Use of meldonium violates none of the three basic WADA criteria for considering substances or methods for their inclusion in the Prohibited list. JSC Grindeks will make further efforts to have meldonium removed from the Prohibited list.

It should also be noted that inclusion of meldonium in the Prohibited list does not change the fact that Mildronate is a drug of a high quality, safety and efficacy. Until now it has been available to everyone, including athletes, to prevent the negative effects caused by physical and psycho-emotional overload.

Why is Mildronate not licensed by the European Medicines Agency or the Food and Drug Administration?

Mildronate (INN: meldonium) has been marketed since 1984 in the former USSR countries. Latvia joined the EU in 2004. Mildronate got the status of well-established use medicine in Latvia (for example, like aspirin), because of its proved efficacy and safety. According to Article 10a of Directive 2001/83/EC it is possible to replace results of the pre-clinical and clinical trials by detailed references to published scientific literature (information available in the public domain) if it can be demonstrated that the active substances of a medical product have been in well-established medicinal use within the Community for at least ten years, with recognised efficacy and an acceptable level of safety. In this regard, the provisions of Annex I of Directive 2001/83/EC shall apply.

To register medication in USA through FDA, a marketing authorization applicant has to conduct full cycle clinical trials in the US prior to submitting an application adequate to contemporary requirements, which has not been done for Mildronate preparations. To conduct a full cycle of registration which is a process demanding a long period of time and resources for a product that has lost its patent protection already in 2006 would not be expediently for majority of pharmaceutical companies, including JSC Grindeks. However, JSC Grindeks considers to expand availability of Mildronate in other countries.

When did Mildronate come out on the market?

Mildronate has been successfully marketed since 1984 in formed USSR countries, and later in Latvia, Lithuania, Russia and other CIS countries.

In which countries is Mildronate approved for use and available?

JSC Grindeks has registered Mildronate in Albania, Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kosovo, Kyrgyzstan, Latvia, Lithuania, Moldova, Mongolia, Russia, Tajikistan, Turkmenistan, Ukraine and Uzbekistan.

What kind of published data exists on the efficacy of meldonium?

There are many articles available on PubMed and other scientific sources on efficacy and safety of meldonium, both preclinical and clinical. JSC Grindeks has conducted randomized, double-blind, placebo controlled multinational phase II and III clinical studies which can be found at EU Clinical Trial Register (EudraCT Number: 2007-005179-32 and EudraCT Number: 2004-001611-58 respectively).