Hartil tablets 5mg bl N7x2 Egis/Actavis

"Actavis" is a force that acts

— When a child exhibits extraordinary abilities, he is called a child prodigy. What do you call a company that operates and develops so dynamically that in recent years it has demonstrated double growth rates?

Y.T.:

This is because already in its very name there is a call for constant growth. We wanted to give the company a name that would reflect our desire for dynamic development and quick resolution of issues. In addition, a necessary quality of the new name should have been its applicability and adequacy in any country in the world. The name "Actavis" comes from two Latin words - "acta", meaning "action" and "vis", meaning "strength".

— You ambitiously declare your intention to become a leader in the international generics market. The company's operating results and its latest acquisitions prove the seriousness of this strategy beyond just words. Are there any difficulties in managing such a huge company?

Y.T.:

6 years ago, our company, which at that time was called Pharmaco, faced with the problem of the limited domestic market in Iceland, acquired three in Bulgaria, and things gradually went up. In 2002, it merged with another Icelandic pharmaceutical company. So, acquiring and expanding, we moved forward. The story of Actavis is a story of a beautiful dream, great work and determination to achieve success. These values ​​are shared by each member of the international Actavis team. After all, we are all one team of like-minded people. And such people, regardless of the country, are always easier to lead. It is the flexible mind of the employees and the flexible organizational structure of Actavis that have become the main competitive advantages of the company. Our management philosophy is transparent: love success, not your own rank, always welcome change, create value every day and develop in order to succeed. Thanks solely to the fact that the company employs capable, independent and creative people, we constantly find the best ways to achieve our goals.

— By the way, about goals. What is the main strategic goal of Actavis?

Y.T.:

At the turn of the second and third millennia, the company outlined its global goal - to become a world leader in the development and production of high-quality generic drugs, and today Actavis is one of the five largest generic companies in the world. Actavis products help millions of people around the world; the company's share of the global pharmaceutical generic market is 4%. Is our strategic goal a blind and uncontrollable thirst for victory at any cost? No, ambition alone is not enough here. Many companies have a strong desire to win, but they fail because they do not actively develop strategies and implement them.

Endurance and tolerance for the unexpected are part of our daily work and help us understand that reaching the top is just the beginning of the journey. It is very important to continue to remain worthy of this peak. If you fall, get up and keep going. The future doesn't wait. Expect a lot from people, expect even more from yourself, and never take “no” as the final answer in business. That's all wisdom.

— The group’s composition is constantly expanding due to new acquisitions. What criteria are used to select future group members?

Y.T.:

The global community is following Actavis' successes with interest. In 6 years, the company has grown from a small wholesale and manufacturing association in Iceland with a staff of 146 people into one of the leaders in the global generics market, bringing together 24 companies and 10,000 employees. In 1999, the company's turnover was 57 million euros, the expected forecast for 2006 was 1.3 billion euros. Therefore, Actavis is rightfully considered one of the fastest growing pharmaceutical companies in the world.

In order to become a leader, it is necessary to strengthen international power through strong regional positions, which is why Actavis makes strategic acquisitions, taking into account the local achievements of the “challengers”. Each of the companies that joined the Actavis group has something to be proud of. They have a lot in common - they are often stable companies with an impeccable reputation in domestic markets. Today we are united by common efforts and thanks to this we have become more effective than ever.

To be a champion, you need to be aggressive in your pricing, and we do that by acquiring new companies and driving down costs in drug research, development and manufacturing. Unlike many of our competitors, when making strategic expansions, we take into account the companies' ability to influence the main pricing criteria - the cost of raw materials and auxiliary materials, development, production and sales costs, looking for opportunities for savings.

Thus, we have the advantage of good knowledge of domestic markets, which makes us more flexible, responsive and ready to respond to customer needs, and the main reason for this is that our strength is supported by a strong local position.

Expansion of the group through the acquisition of pharmaceutical companies around the world is one of the company's primary strategic objectives. The latest acquisition took place at the end of March 2006, when the Romanian generic pharmaceutical company, which specializes in the production and marketing of drugs for use in oncology, joined the international Actavis family. Its range of more than 30 drugs organically complements Actavis’ global product portfolio. With the acquisition of the Romanian company, the production of drugs for use in oncology has become another area of ​​activity for us.

V.M.:

Each new acquisition allows us to strengthen Actavis’ position in the national markets of manufacturing companies, as well as to consistently expand the company’s product range. In addition, the factor of individual territorial preferences of our clients is also important. Traditionally, patients trust drugs from domestic manufacturers more, the brands of which are familiar to them for a long time. Some time after acquiring an enterprise in any country, the Actavis trademark also becomes “native” for its residents, and this creates significant advantages when promoting new products to the market.

— What achievements can the Ukrainian representative office of Actavis be proud of today?

V.M.:

The group did not come to Ukraine out of nowhere; a representative office had been operating in our country for several years. Actavis began to build its business on the Ukrainian market, using the platform and potential that had been created over the years. As the head of the Ukrainian representative office, I am very pleased to note the high results of our team’s work: sales volume has increased several times, the company enjoys well-deserved prestige among partners and consumers, our entire business has undergone significant restructuring both in terms of product distribution and marketing. Thanks to active and fruitful collaboration with the advertising agency Media Partner, we were able to implement a number of successful projects to promote the group’s drugs on the Ukrainian market.

By using international best practices, business processes have become more modern. Today we profess completely new principles and use a progressive system of personnel selection and motivation. The renewed team of the representative office was formed on the principles of healthy ambition and the desire to grow and develop. We are making every effort to further strengthen Actavis’ position in the Ukrainian market. Our team is driven, first of all, by the desire to prove that we are the best and can achieve results that no one has been able to achieve before. All this allows us to demonstrate a significant increase in quantitative indicators in Ukraine and change for the better qualitatively.

— How did the active acquisition of pharmaceutical enterprises affect the group’s product portfolio in Ukraine?

V.V.:

Geographically, Actavis' portfolio is quite diversified. The modern range of Actavis drugs in the post-Soviet countries and a number of Eastern European countries is largely identical and is represented by drugs manufactured by . Today, the result of dynamic extensive development is the beginning of intensive work, which consists of searching for the most interesting and promising products in each market, after which the international portfolio of Actavis should become more universal. The Ukrainian representative office of Actavis is also actively working to introduce new products to the domestic market. In the very near future, two new drugs produced in Bulgaria and Germany are expected to appear in Ukraine, and by the end of the year it is planned to expand the geography of the Ukrainian portfolio to include products produced by enterprises in Iceland, Malta, Serbia, the USA, India, China and France. In total, 10 new drugs from the group are planned to appear on the market in 2006. To summarize, we can say that over time, Actavis’ worldwide portfolio will become more structured, and some older products will be replaced by more promising ones.

“But there has always been quite tough competition in the generics market. What principles does the Ukrainian representative office of Actavis follow when choosing drugs to bring to the country’s market?

V.V.:

The choice is determined, first of all, by the demand for a particular drug. To determine it, we quite widely use the developments and capabilities of our external service: contacts with key representatives of the country’s medical community, as well as with employees of medical institutions and pharmacies. Moreover, very often our colleagues themselves suggest the need to move in one direction or another regarding expanding the product portfolio. We compare the information received with our own market research, the capabilities of our production and research departments, and decide on the advisability of introducing a new drug to the market. There are situations when a need for a new drug is identified, but Actavis does not produce it. In such cases, it is sometimes advisable to produce such a drug at another enterprise under a contract. Today we do not have such products on the Ukrainian market, but they will also appear in the very near future.

The current range of Actavis in Ukraine is represented mainly by over-the-counter drugs. All of them have a long history of application in practice by domestic specialists. The best-selling products are analgesics, vitamin preparations, drugs acting on the nervous system, affecting the digestive system and metabolism, as well as drugs for topical use: ointments and gels. If we talk about the expected new products, these drugs have already been well studied and, as a rule, have proven bioequivalence. However, when introducing them to the market, we plan to conduct research in Ukraine, since our doctors are primarily interested in the experience of use in domestic medical centers. When introducing new drugs to the market, the emphasis will be somewhat shifted towards prescription drugs, in particular, those used in neurology and cardiology.

— It is generally accepted that, for a number of reasons, imported drugs are significantly more expensive than domestic ones, but the prices for the group’s products are quite “democratic.” Tell us about the pricing policy followed by Actavis in Ukraine, taking into account the launch of new products on the market.

V.V.:

Indeed, Actavis products presented on the Ukrainian market today are available to a wide range of consumers. Despite fierce competition, we manage to maintain prices for our drugs at a level acceptable to our clients. It is obvious that after the group’s portfolio is replenished with new drugs, the average cost of a package will increase, but will remain quite competitive. To compensate for the increased cost of drugs, Actavis will offer consumers some special properties of the new products, which, I am sure, will be appreciated.

— What is the internal policy of Actavis based on? While caring about customers, how much does the company care about its own employees?

Y.T.:

Our slogan “Creating value in pharmaceuticals” clearly reflects the mission of Actavis.
We create value and benefits for our customers by providing the market with high quality generic products; for our investors and shareholders by creating one of the fastest growing companies in our industry; as well as for our employees - providing reliable and promising jobs. Our goal is to be number one in all major pharmaceutical markets. But this concept is quite ambiguous. It can mean dominating a market or becoming the most profitable and innovative company in its industry. Or it can simply mean the best place to work...
The main idea of ​​working here is a clear understanding of personal responsibility - whatever you say, it is our intelligent, independent and creative employees who constantly find the best ways to achieve their goals. To create this force of the best of the best, we carefully select new employees and actively train staff so that they can reach their full potential and thereby help the company achieve its goals.

— What unites the people who form the team of the group’s representative office in Ukraine? What makes this team special?

Y.T.:

The democratic leadership style in our company creates an atmosphere of creativity and contributes to the realization of each employee and the regional team as a whole. The Ukrainian team is very independent. We provide him with opportunities, and he reveals his potential. This is truly an example for other representative offices in terms of initiative, team spirit and efficiency. Probably, it is these qualities that help him to be an “excellent” among more than 30 Actavis representative offices around the world.

V.M.:

Despite the rather rigid organizational structure and executive discipline, in the group the spirit of team partnership prevails over formal business processes. Actavis does not employ people who do not believe in the success of what they do. The employees of the Ukrainian representative office are energetic and proactive, and this, combined with effective mutual support, gives us a significant advantage over our competitors. In our work we profess the principle: “Don’t love your position, but love the work you do.” An important motivational tool, along with the material component, is moral satisfaction from the work performed. It is very important for every employee that he works in the right team and does the right things that come out in the best possible way. This is typical not only for the Ukrainian representative office, but also for the entire group as a whole.

K.Ch.

: In 2005, the team of the external service of the representative office grew three times, today it consists of 47 people: 42 medical representatives, the rest are regional managers supervising work in the field. External service employees work with doctors and pharmacists in pharmacies - specialists receive from our medical representatives all the necessary information about Actavis products, allowing them to make the right choice when making prescriptions. By increasing the staff of the external service of the representative office, we ensured a stable presence and effective promotion of the group’s products in all regional centers and regions of Ukraine.

— You say that the team of Actavis employees is a team of like-minded people and professionals. How are personnel recruited and trained?

Y.T.:

The Human Resources Department coordinates activities in this area throughout the group. It is also responsible for conducting training for administrative staff and carrying out management activities. The Actavis Academy is our own training and education program that complements the vocational training system that operates in each of the group's regional divisions.

Training is an important part of the group's daily activities. It includes an induction course for new employees, various projects aimed at developing the skills and abilities necessary for Actavis to become the first in today's highly competitive environment.

Among the initiatives of the Actavis Academy planned for 2006 are the implementation of programs for effective management activities and the development of leadership skills. The purpose of the Effective Management Course is to develop a shared view of how Actavis operates and to continue to build a culture of corporate governance.

K.Ch.:

The Ukrainian representative office of Actavis has created a special training program for medical representatives. It includes an in-depth study of the company’s products, general medical issues and, of course, we make sure that each of our employees receives professional training in communication skills.

In addition, we effectively use the institute of our regional managers, because these are the people who know from their own experience the specifics of the work of medical representatives. They are constantly busy raising the level of training of their subordinates; the regional manager devotes 80% of his working time to working together with medical representatives - these are joint visits to medical and pharmacy institutions, working with key clients, etc. This allows all our team players to grow professionally, gain irreplaceable practical experience and share it with their colleagues.

A favorable microclimate in our team and a positive attitude towards work are also an important component of the success of the entire team of the Ukrainian representative office of Actavis. The company has an effective two-way communication mechanism; Initiative coming from our employees is always welcome. Based on the results of anonymous surveys of employees regarding their opinions about working conditions, principles and internal policies of the company, we are making the necessary efforts to improve the internal corporate interaction system. We are very pleased with the fact that, according to recent surveys, the vast majority of our employees express satisfaction with their own status at . Now our task is to maintain the achieved level of interaction efficiency and further motivate the company’s personnel to even more outstanding achievements.

— One of the important factors for the successful operation of any pharmaceutical company is effective cooperation with distributors. How does the group’s representative office in Ukraine build its policy in this regard?

V.M.:

The company revised its organizational strategy for interaction with distributors, defining for itself a number of priority criteria. First of all, this is complete geographical coverage of the territory of Ukraine, the size of the business, the principles that guide the distributor in its work (pricing, financial discipline), and, also important, previous positive experience of working together. We believe that our company has made a serious step forward in the field of distribution, and the best proof of this is the significant increase in our turnover. One of the key factors for such success is the openness and transparency of the partnership policy with distribution companies: we provide everyone with equal terms of cooperation.

K.Ch.:

Maximum reduction of the time interval between the moment of receipt of the application and the fact of delivery of the product to the customer was the main goal of the new strategy. We managed to solve this problem by creating a flexible forecasting system and forming inventory in the warehouses of our partners. Invaluable assistance in our work is provided by , whose customs-licensed warehouse has been used for storing the group’s products for several years now. In my opinion, distribution companies are links in the same chain; together we solve one problem - the uninterrupted supply of high-quality drugs to Ukrainian consumers.

— Tell us about the priority methods for promoting Actavis products on the Ukrainian market in the context of increasing the company’s sales level.

K.Ch.:

Taking into account the specifics of the group’s product portfolio and the prospects for its expansion, the efforts of the external service are aimed primarily at doctors of various specialties. Initially, we worked only with general practitioners, then specialized specialists were added to them: neurologists, ENT doctors, cardiologists, etc. The main task of medical representatives is to timely convey to doctors and pharmacists the necessary information about our products, so that the specialist can easily offer the patient the necessary drug. It is through constant targeted work “in the fields” that customer loyalty to the company’s products is formed. In future work, we place our main hopes on prescription products, and when promoting them, we place the main emphasis on prescribing doctors.

V.V.:

The increase in sales volumes is largely due to the growth of the Ukrainian pharmaceutical market as a whole. By expanding our geographic coverage, we are able to provide information about Actavis products to a larger number of specialists, including doctors with whom we have not worked before. An important component of commercial success is methods of promoting products among consumers. We try to make maximum use of all available advertising media - these are popular and specialized press, television and radio, outdoor advertising, advertising in transport, etc. The combination of different promotion methods is selected individually for each specific drug. One of the best Ukrainian advertising agencies, with which we have been working closely for the second year, helps us in this.

— Recently, the group has been paying significant attention to promoting its corporate brand. Will this trend continue in the future?

V.V.:

Not long ago, we changed the design of the packaging of our drugs, after which we had every reason to start promoting the Actavis corporate brand in Ukraine.
The campaign to promote the corporate brand has just begun, it is designed to prevent potential confusion among our partners and consumers -
from now on, the group's products should be associated with a new brand, high quality and first-class service. Work on the corporate image is already bearing first fruits: our partners and clients know that Actavis is the legal successor of Balkanpharma in Ukraine and call Actavis one of the most dynamic companies on the market.

— What are the group’s prospects on the Ukrainian pharmaceutical market?

V.M.:

Clearly following the company’s global goal to become a leader in the generic market, we plan to dynamically expand the Ukrainian product portfolio through drugs from various enterprises that form the Actavis family. I can say that active negotiations are currently underway on further acquisitions; it is possible that any enterprise located in one of the CIS countries will join the group. We will make maximum use of Actavis’ international potential to achieve the best results in Ukraine.

V.V.:

On behalf of the representative office in Ukraine, I would like to sincerely thank all our partners and consumers for their high trust and fruitful cooperation. We owe much of our achievements to distribution companies. However, not the last place in Actavis’ success strategy is occupied by doctors and pharmacists: by listening to their wishes and recommendations, trying to understand and predict their needs, we build the work of the representative office’s marketing service. Together with my colleagues, I am pleased every day to know that we work for a company whose products are of high quality and therefore are respected by both consumers and medical professionals throughout the country.

— Despite the fact that Iceland and Ukraine are geographically located far from each other, there are historical facts that prove the connection between our peoples. Is this connection noticeable today - in the 21st century?

Y.T.:

You are absolutely right. Almost in the same time period, the first settlers appeared on the island of Iceland and Kievan Rus was founded. The famous Viking campaigns on ancient Russian lands went down in history as “The Path from the Varangians to the Greeks,” and the Norman Rurik family occupied the princely throne of the powerful Slavic state for a long time.

I have a special relationship with Kyiv. In this city the spirit of the times is felt like no other place. Despite the fact that Kyiv is a European metropolis, the domes of centuries-old cathedrals and churches make you think about the eternal...

Ukraine and Iceland today are two people close in spirit: Ukrainians are as hospitable, open and hardworking as the Icelanders. And these qualities undoubtedly help us in our work. It is easy and pleasant to do business with like-minded people. o

Vitaly Shevchenko, photo by Igor Krivinsky and provided by the representative office in Ukraine

Imatinib-Actavis

Patients with advanced malignancies may have a variety of medical conditions that make it difficult to assess the cause-and-effect relationship of an adverse reaction to imatinib due to the multiple symptoms associated with the disease, its progression, and concomitant use of multiple drugs.

In clinical trials of CML, 2.4% of patients with newly diagnosed disease discontinued treatment due to adverse reactions. 4% of patients with the disease in the chronic phase when previous interferon therapy is ineffective. 4% of patients in the acceleration phase with ineffectiveness of previous interferon therapy and 5% of patients in the blast crisis phase with ineffectiveness of previous interferon therapy. In clinical trials of imatinib for the treatment of GIST, 4% of patients discontinued treatment due to adverse reactions.

The adverse reaction profile differed between the two indications. Patients with CML are more likely to develop myelosuppression compared to patients with GIST. which may be related to the presence of the disease itself. 7 (5%) patients with unresectable and/or metastatic GISTs experienced overall toxicity grade 3/4 bleeding: 3 patients with gastrointestinal bleeding. 3 patients with intratumoral bleeding, both types of bleeding were observed in 1 patient. A gastrointestinal tumor can be a source of gastrointestinal bleeding (see section "Special Instructions"). Gastrointestinal and intratumoral bleeding can be serious and sometimes fatal. The most common adverse events (>10%) associated with imatinib. in both cases there were: mild nausea, vomiting, diarrhea, abdominal pain, weakness, myalgia, muscle cramps, rash. Superficial edema was a common adverse reaction in all studies and was predominantly described as periorbital edema or lower extremity edema. However, this edema was rarely severe and was resolved by taking diuretics, taking other appropriate measures to eliminate edema, or reducing the dose of imatinib.

When taking imatinib in combination with high doses of chemotherapy in patients with Ph+ ALL, temporary manifestations of hepatotoxicity were observed in the form of an increase in the activity of liver transaminases and hyperbilirubinemia.

Several adverse reactions, collectively described as “fluid retention,” may occur: pleural effusion, ascites, pulmonary edema, and rapid weight gain with or without superficial edema. These reactions can usually be eliminated by temporarily stopping imatinib, taking diuretics, or taking other appropriate measures to eliminate edema. However, some of these reactions may be severe or life-threatening. Fatalities have been reported in patients in blast crisis who had a medical history of pleural effusion, congestive heart failure, and renal failure. No differences were identified in the safety profile of imatinib in the pediatric population.

During clinical studies, patients experienced the following adverse events, listed below by organ and system, indicating the frequency of their occurrence: very often (≥1/10), often (≥1/100, <1/10), infrequently (≥1/10). 1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency unknown (cannot be determined from available data).

In each subgroup, adverse reactions are listed in order of frequency of occurrence, with the most common occurring first.

Infectious and parasitic diseases: infrequently - herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, inflammation of the subcutaneous tissue, upper respiratory tract infections, influenza, urinary tract infections, gastroenteritis, sepsis: rarely - mycoses.

Benign, malignant and unspecified neoplasms (including polyps and cysts): rarely - tumor lysis syndrome.

From the blood and lymphatic system: very often - neutropenia, thrombocytopenia, anemia: often - pancytopenia, febrile neutropenia: infrequently thrombocythemia, lymphopenia, suppression of bone marrow hematopoiesis, eosinophilia, lymphadenopathy; rarely - hemolytic anemia.

Metabolism and nutrition: often - anorexia; infrequently - hypokalemia. increased appetite, hypophosphatemia. loss of appetite, dehydration, gout, hyperuricemia. hypercalcemia. hyperglycemia. hyponatremia: rarely hyperkalemia, hypomagnesemia.

Mental disorders: often - insomnia; infrequently - depression, decreased libido, anxiety; rarely - confusion.

From the nervous system: very often - headache2; often - dizziness, paresthesia, taste disturbance, hypoesthesia: infrequently - migraine, drowsiness, fainting, peripheral neuropathy, memory impairment, sciatica, restless legs syndrome, tremor, hemorrhagic stroke; rarely - increased intracranial pressure, convulsions, optic neuritis.

From the organ of vision: often - swelling of the eyelids, increased lacrimation, hemorrhage in the conjunctiva, conjunctivitis, dry eye syndrome, blurred vision; uncommon: eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema; rarely - cataracts, glaucoma, papilledema.

From the organ of hearing and labyrinthine disorders: infrequently - vertigo, tinnitus, hearing loss.

From the heart: infrequently - palpitations, tachycardia, congestive heart failure3, pulmonary edema: rarely - arrhythmias, atrial fibrillation, sudden cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.

From the side of blood vessels: often - “hot flashes”4, hemorrhages4; uncommon - increased blood pressure, hematomas, subdural hematoma, cold extremities, decreased blood pressure, Raynaud's syndrome.

From the respiratory system, chest organs, mediastinum: often shortness of breath, nosebleeds, cough: infrequently - pleural effusion5, pain in the pharynx or larynx, pharyngitis: rarely - pleural pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhages.

From the digestive system: very often - nausea, diarrhea, vomiting, dyspepsia, abdominal pain6: often - flatulence, bloating, gastroesophageal reflux, constipation, dry mouth, gastritis: infrequently - stomatitis, ulceration of the oral mucosa, gastrointestinal tract intestinal bleeding7, belching, melena, esophagitis, ascites, gastric ulcer, vomiting blood, cheilitis. dysphagia, pancreatitis: rarely - colitis, paralytic/obstructive intestinal obstruction, inflammation of the intestine.

From the liver and biliary tract: often - increased activity of “liver” transaminases; infrequently - hyperbilirubinemia. hepatitis, jaundice; rarely liver failure9, liver necrosis9.

From the skin and subcutaneous tissues: very often - periorbital edema, dermatitis, eczema, skin rash; often - itching, swelling of the face, dry skin, erythema, alopecia, night sweats, photosensitivity reactions; uncommon - pustular rash, bruising, increased sweating, urticaria, ecchymosis, increased susceptibility to hematoma formation, hypotrichosis, skin hypopigmentation, exfoliative dermatitis, nail damage, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous rash; rarely - acute febrile neutrophilic dermatosis (Sweet's syndrome), discoloration of nails, angioedema, vesicular rash, erythema multiforme, leukoclastic vasculitis, Stevens-Johnson syndrome, acute generalized pustular exanthema, drug rash with eosinophilia and systemic symptoms (DRESS).

From the musculoskeletal system and connective tissue: very often muscle spasms and cramps, musculoskeletal pain (including myalgia, arthralgia, bone pain8); often - swelling of the joints; infrequently - stiffness of muscles and joints; rarely - muscle weakness, arthritis, rhabdomyolysis/myopathy; frequency unknown - growth retardation in children.

From the urinary system: uncommon - kidney pain, hematuria, acute renal failure, frequent urination.

From the reproductive system and mammary glands: infrequently - gynecomastia, erectile dysfunction, menorrhagia. menstrual irregularities, sexual dysfunction, nipple pain, breast enlargement, scrotal swelling; rarely bleeding from a corpus luteum/ovarian cyst.

General disorders and disorders at the injection site: very often - fluid retention, swelling, increased fatigue; often - weakness, fever, anasarca, chills, trembling; infrequently - chest pain, general malaise.

From laboratory parameters: very often - increase in body weight; often - weight loss; uncommon - increased serum creatinine, creatine phosphokinase, lactate dehydrogenase, alkaline phosphatase activity; rarely - increased amylase activity in blood plasma.

1 - Pneumonia was most often observed in patients with CML in the accelerated phase, blast crisis and with inoperable and/or metastatic malignant stromal tumors of the gastrointestinal tract.

2 -Headache was most often observed in patients with inoperable and/or metastatic malignant tumors of the gastrointestinal tract.

3 - Adverse cardiac events, including congestive heart failure, were more often observed in patients with CML in the accelerated phase and during blast crisis compared with patients with CML in the chronic phase (follow-up duration - 1 year).

4- “Hot flashes” were most often observed in patients with inoperable and/or metastatic malignant stromal tumors of the gastrointestinal tract: bleeding (hematomas, hemorrhages) were most often observed in patients with CML in the accelerated phase, blast crisis and with inoperable and/or metastatic malignant stromal tumors Gastrointestinal tract.

5 -Pleural effusion was more often observed in patients with gastrointestinal stromal tumors and CML in the accelerated phase and during blast crisis compared with patients with CML in the chronic phase.

6/7- Abdominal pain and gastrointestinal bleeding were most often observed in patients with unresectable and/or metastatic malignant gastrointestinal stromal tumors.

8 — Musculoskeletal pain and associated adverse events (including myalgia, arthralgia, bone pain) were more often observed in patients with CML compared with patients with inoperable and/or metastatic malignant stromal tumors of the gastrointestinal tract.

9 - Isolated fatal cases of liver failure and liver necrosis have been reported.

When using imatinib in clinical practice, as well as during additional clinical studies, the following adverse reactions were observed. Because information on adverse reactions was obtained as spontaneous reports from patients whose population size is not precisely known, it is not always possible to determine the incidence of adverse reactions or the relationship between the use of imatinib and these adverse reactions.

Post-registration experience of use

Benign, malignant and unspecified neoplasms (including cysts and polyps): frequency unknown - tumor bleeding/tumor necrosis.

From the immune system: frequency unknown - anaphylactic shock.

From the nervous system: frequency unknown - cerebral edema.

On the part of the organ of vision: frequency unknown - hemorrhages into the vitreous body.

From the heart: frequency unknown - pericarditis, cardiac tamponade.

Vascular disorders: frequency unknown - thrombosis/embolism.

From the respiratory system, chest organs, mediastinum: frequency unknown - acute respiratory failure1, interstitial lung disease.

From the gastrointestinal tract: rarely - vascular ectasia of the gastric antrum (GAVE syndrome); frequency unknown - paralytic/obstructive intestinal obstruction, gastrointestinal perforation, diverticulum pt.

From the skin and subcutaneous tissues: frequency unknown - palmoplantar erythrodysesthesia; lichenoid keratosis, lichen planus; toxic epidermal necrolysis; drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: frequency unknown - avascular necrosis/necrosis of the femoral head: growth retardation in children.

1 - There are isolated reports of the development of severe acute respiratory failure with a fatal outcome in patients with severe infectious diseases, severe neutropenia and other serious concomitant diseases.

Description of selected adverse reactions

Inhibition of hematopoiesis

In patients with CML, cytopenia, especially neutropenia and thrombocytopenia, was observed in all studies, and the incidence was higher with high doses of imatinib > 750 mg (phase I). However, the frequency of cytopenia also depended significantly on the stage of the disease. The incidence of grade 3 or 4 neutropenia (absolute neutrophil count < 1.0x109/L) and thrombocytopenia (platelet count < 50x109/L) was 4 and 6 times higher in the blast crisis and acceleration phases (59-64% and 44-63 % for neutropenia and thrombocytopenia, respectively) compared with newly diagnosed CML in the chronic phase (16.7% neutropenia and 8.9% thrombocytopenia). In patients with newly diagnosed CML in the chronic phase, grade 4 neutropenia (absolute neutrophil count <0.5x109/L) and thrombocytopenia (platelet count <10x109/L) were observed in 3.6% and less than 1% of patients, respectively. The median duration of episodes of neutropenia and thrombocytopenia typically ranged from 2 to 3 weeks and from 3 to 4 weeks, respectively. These adverse events are usually relieved by either reducing the dose of imatinib. or temporary discontinuation of its use, but in rare cases they may require complete discontinuation of imatinib or its discontinuation for a long period. In pediatric patients with CML, the most common toxicity observed was grade 3 or 4 cytopenia, including neutropenia, thrombocytopenia, and anemia. These reactions mainly occurred in the first months of treatment.

In general, the suppression of hematopoiesis during the use of imatinib in patients with CML was reversible and in most cases did not require discontinuation of imatinib or reduction in its dose. Discontinuation of imatinib was required in a small number of cases. Such phenomena as pancytopenia, lymphopenia and suppression of hematopoiesis were also noted.

In studies of patients with unresectable and/or metastatic malignant GISTs, grade 3 and 4 anemia was reported in 5.4% and 0.7% of patients, respectively. This phenomenon, at least in some patients, may be associated with gastrointestinal bleeding or intratumoral bleeding. Grade 3 and 4 neutropenia was observed in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patients with grade 4 thrombocytopenia were identified. The decrease in the number of leukocytes and neutrophils occurred mainly during the first six weeks of therapy, with relatively stable values ​​being established after this period of time.

Biochemical blood parameters

Severe increases in hepatic transaminase activity (<5%) or increases in bilirubin concentrations (<1%) were observed in patients with CML and these adverse events generally resolved after dose reduction of imatinib or treatment interruption (median duration of these adverse events was approximately one week). Treatment was discontinued or interrupted long-term due to abnormal liver function laboratory tests in less than 1% of patients with CML. 6.8% of patients with GIST had a grade 3 or 4 increase in alanine aminotransferase activity and 4.8% had a grade 3 or 4 increase in aspartate aminotransferase activity. The increase in bilirubin concentration was less than 3% of patients.

There have been reports of cytolytic and cholestatic hepatitis and liver failure, some fatal, including a patient taking high doses of paracetamol.

Severe adverse events from the respiratory system

Severe (sometimes fatal) adverse events have been reported with imatinib: acute respiratory failure, pulmonary hypertension, interstitial lung disease, and pulmonary fibrosis. Concomitant pathology of the cardiovascular and respiratory systems may aggravate the severity of the adverse event.