Krka’s Added-value Generic Medications

    Authors

    Abstract

    In its 65-year history, Krka has grown from a small pharmaceutical laboratory to become one of the leading generic pharmaceutical companies in the world. Krka’s innovative, added-value generic medications are developed using the company’s own know-how. This ensures that they hold certain key advantages over competitor products, resulting from the development of new technologies used in the production of active ingredients and dosage forms. When planning our product portfolio, we closely monitor the most common diseases in the modern world. We allow doctors and patients to choose from a wide variety of packaging, strengths, and single-pill combinations. The therapeutic equivalence of our medications with the originator’s medications is demonstrated by in vivo bioequivalence studies. The results of numerous clinical studies show that our medications are effective and well-tolerated by patients in clinical practice.

    Keywords

    added-value generics, quality, vertically integrated production, clinical studies

    DOI

    https://doi.org/10.15836/ccar2019.146

    Full Text

    ## Introduction In its 65-year history, Krka has grown from a small pharmaceutical laboratory employing less than 10 people to become one of the leading generic pharmaceutical companies in the world employing more than 12,000 people. Our core business is the production and sale of prescription pharmaceuticals (more than 80%), non-prescription products (almost 10%), and animal health products (5%). ( 1 ) When planning our product portfolio, we closely monitor the most common diseases in the modern world. Cardiovascular medications are our most important therapeutic group of prescription medications, with 22 million patients treated every day. ( 1 , 2 ) Krka produces high-quality, effective, and safe medications that are marketed under the company’s own brands. Our vertically integrated production model allows us to have complete oversight of the whole production process from the active ingredient to the finished product. Our focus is on developing innovative, added-value generic medications, which are the result of our own know-how. This ensures that our products have advantages of key importance for several years after they have been introduced to the market. They result from the development of new technologies used in the production of active ingredients and dosage forms. ( 1 ) ## Quality The active ingredients most commonly built into Krka’s generic medications are synthesized using our own biosynthesis and chemical synthesis processes. We have more than 350 patent-protected innovations for which we have obtained several patents in various European, American, and Asian countries. The Chamber of Commerce and Industry of Slovenia has presented Krka with a number of awards for innovation, including the Golden Award for a bilayer tablet, a single-pill combination of two active ingredients used in the treatment of hypertension. This innovation is based on integrating several innovative approaches in the synthesis of telmisartan, the development of the formulation, and the production of bilayer tablets containing telmisartan and hydrochlorothiazide, which act synergistically on blood pressure ( Figure 1 ). The innovative product ensures quick and reliable release of both physically separated active ingredients built into the bilayer tablet. This guarantees that both active ingredients remain chemically stable and that the product’s quality is sustained. ( 1 ) Innovative formulation of the single-pill combination of 80 mg telmisartan and 25 mg hydrochlorothiazide, which releases two active ingredients physically separated from each other in a bilayer tablet. The high quality of our telmisartan was also confirmed by the recent withdrawal of some products containing valsartan, losartan, and irbesartan due to nitrosamine impurities in Europe and in the USA. Several producers of sartan products had to withdraw their products from the markets, while Krka’s sartan products (products with active substances valsartan, candesartan, losartan, olmesartan, and irbesartan) remained on the markets due to their proven high quality. We have scientifically evaluated routes of synthesis for all active sartan substances. The results have shown that there are no conditions for the formation of any nitrosamine impurities. We have implemented all necessary measures and conducted rigorous testing to prove no quantifiable levels of nitrosamine impurities are present in our sartans. ( 2 ) ## New treatment options By offering new dosage strengths and various single-pill combinations, we allow doctors to select the most appropriate medication for their patients. We were the first company to launch 30 mg and 60 mg strengths of atorvastatin and 15 mg and 30 mg strengths of rosuvastatin. With more than 70 single-pill combinations of two or three antihypertensives in various strengths, we provide doctors with the best treatment option for each of their patients with arterial hypertension. Among perindopril combinations, the latest is the triple single-pill combination containing perindopril, indapamide, and amlodipine. A single-pill combination of active substances from three recommended groups of antihypertensives in one tablet, an ACE inhibitor, a diuretic, and a calcium channel blocker, allows the product to be universally used in the treatment of hypertension, which facilitates treatment. Krka was the first pharmaceutical company in the world to offer this triple combination to doctors and patients. ( 1 ) We are aware of the importance of preventing cardiovascular events and of the need for new treatment methods for patients with several risk factors. More than half of all people with high blood pressure, for example, also have high cholesterol. When these two risk factors occur together, their impact on disease progression is not only added but multiplied. Therefore, our newest products are single-pill combinations of medications for concurrent treatment of high cholesterol and blood pressure with a single tablet a day. Single-pill combinations of medications that lower lipid and blood pressure help improve patient compliance and thus more effectively prevent occurrences of cardiovascular events. ## Therapeutic equivalence A Krka medication is equal to the originator’s medication. Their pharmaceutical equivalence is demonstrated with in vitro dissolution testing, while in vivo therapeutic equivalence is demonstrated with bioequivalence studies; in both cases we directly compare our medication with the originator’s medication. Krka’s bioequivalence studies are performed in several European and North American countries. They are performed at a high scientific and professional level in line with strict international requirements (Good Clinical Practice (GCP), Good Laboratory Practice (GLP), European Medicines Agency and Food and Drug Administration guidelines) for clinical trials regarding medical, regulatory, and ethical standards. The studies are performed on locations compliant with GCP and GLP, which are regularly inspected by the European and American regulatory authorities. ( 1 ) Krka’s rosuvastatin has a built-in active ingredient that was synthesized using our own synthesis procedure, with the tablet wrapped in an innovative film coating. Therapeutic equivalence with the reference rosuvastatin was proven with a bioequivalence study ( Figure 2 ). ( 3 ) Bioequivalence study of Krka’s rosuvastatin 20 mg versus reference rosuvastatin 20 mg. ## Efficacy and safety in clinical practice After a medication has been launched on the market, we regularly monitor its efficacy and safety in everyday practice by conducting clinical studies. In this way we obtain more in-depth data and give doctors an opportunity to get acquainted with our medications and thus acquire valuable experience. Several international interventional clinical studies have been conducted with our cardiovascular medications, such as INTER-ARS (Atoris), HEMERA (Ampril and Lorista and their single-pill combinations), ROSU-PATH (Roswera), VICTORY (Valsacor and its single-pill combinations) to provide answers to various issues. ( 1 ) The latest, still ongoing study is the PRECIOUS study on Krka’s perindopril single-pill combinations (Dalneva, CoDalneva). Its results are expected in the beginning of 2020. ( 2 ) In non-interventional clinical studies, the patients are monitored in everyday clinical practice, where the selection of patients, treatment method, selection of the medication and its prescribing regimen, study design, and patient monitoring do not differ in any way from the established treatment. ( 1 ) The findings of our clinical studies in almost 350,000 patients in 27 countries demonstrate that Krka’s medications are effective and safe in a wide range of patients. ( 2 ) Study findings are documented, analysed, and presented at international congresses (the clinical study VICTORY was presented at the 26 th Meeting of the European Society of Hypertension (ESH 2016) in Paris and the clinical study ROSUPATH at the congress of the European Society of Cardiology (ESC 2016) in Rome) and published in international medical journals. They contribute to the trust the professional public and patients have had in Krka’s medications for decades. ## Conclusion Our aim is to be a reliable partner in health to doctors, pharmacists, and patients by offering them added-value generic medications developed by our own know-how. This assures high quality of the products and their availability in a wide variety of packaging, strengths, and single-pill combinations. The results of numerous clinical studies show that our medications are effective and well-tolerated in clinical practice.

    Cardiologia Croatica
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    Krka’s Added-value Generic Medications

    Professional Article
    Issue5-6
    Published
    Pages146-149
    PDF via DOIhttps://doi.org/10.15836/ccar2019.146
    added-value generics
    quality
    vertically integrated production
    clinical studies

    Authors

    Mateja GrošeljORCIDSlovenia
    Breda Barbič-Žagar*ORCIDSlovenia

    Abstract

    In its 65-year history, Krka has grown from a small pharmaceutical laboratory to become one of the leading generic pharmaceutical companies in the world. Krka’s innovative, added-value generic medications are developed using the company’s own know-how. This ensures that they hold certain key advantages over competitor products, resulting from the development of new technologies used in the production of active ingredients and dosage forms. When planning our product portfolio, we closely monitor the most common diseases in the modern world. We allow doctors and patients to choose from a wide variety of packaging, strengths, and single-pill combinations. The therapeutic equivalence of our medications with the originator’s medications is demonstrated by in vivo bioequivalence studies. The results of numerous clinical studies show that our medications are effective and well-tolerated by patients in clinical practice.

    Full Text

    ## Introduction In its 65-year history, Krka has grown from a small pharmaceutical laboratory employing less than 10 people to become one of the leading generic pharmaceutical companies in the world employing more than 12,000 people. Our core business is the production and sale of prescription pharmaceuticals (more than 80%), non-prescription products (almost 10%), and animal health products (5%). ( 1 ) When planning our product portfolio, we closely monitor the most common diseases in the modern world. Cardiovascular medications are our most important therapeutic group of prescription medications, with 22 million patients treated every day. ( 1 , 2 ) Krka produces high-quality, effective, and safe medications that are marketed under the company’s own brands. Our vertically integrated production model allows us to have complete oversight of the whole production process from the active ingredient to the finished product. Our focus is on developing innovative, added-value generic medications, which are the result of our own know-how. This ensures that our products have advantages of key importance for several years after they have been introduced to the market. They result from the development of new technologies used in the production of active ingredients and dosage forms. ( 1 ) ## Quality The active ingredients most commonly built into Krka’s generic medications are synthesized using our own biosynthesis and chemical synthesis processes. We have more than 350 patent-protected innovations for which we have obtained several patents in various European, American, and Asian countries. The Chamber of Commerce and Industry of Slovenia has presented Krka with a number of awards for innovation, including the Golden Award for a bilayer tablet, a single-pill combination of two active ingredients used in the treatment of hypertension. This innovation is based on integrating several innovative approaches in the synthesis of telmisartan, the development of the formulation, and the production of bilayer tablets containing telmisartan and hydrochlorothiazide, which act synergistically on blood pressure ( Figure 1 ). The innovative product ensures quick and reliable release of both physically separated active ingredients built into the bilayer tablet. This guarantees that both active ingredients remain chemically stable and that the product’s quality is sustained. ( 1 ) Innovative formulation of the single-pill combination of 80 mg telmisartan and 25 mg hydrochlorothiazide, which releases two active ingredients physically separated from each other in a bilayer tablet. The high quality of our telmisartan was also confirmed by the recent withdrawal of some products containing valsartan, losartan, and irbesartan due to nitrosamine impurities in Europe and in the USA. Several producers of sartan products had to withdraw their products from the markets, while Krka’s sartan products (products with active substances valsartan, candesartan, losartan, olmesartan, and irbesartan) remained on the markets due to their proven high quality. We have scientifically evaluated routes of synthesis for all active sartan substances. The results have shown that there are no conditions for the formation of any nitrosamine impurities. We have implemented all necessary measures and conducted rigorous testing to prove no quantifiable levels of nitrosamine impurities are present in our sartans. ( 2 ) ## New treatment options By offering new dosage strengths and various single-pill combinations, we allow doctors to select the most appropriate medication for their patients. We were the first company to launch 30 mg and 60 mg strengths of atorvastatin and 15 mg and 30 mg strengths of rosuvastatin. With more than 70 single-pill combinations of two or three antihypertensives in various strengths, we provide doctors with the best treatment option for each of their patients with arterial hypertension. Among perindopril combinations, the latest is the triple single-pill combination containing perindopril, indapamide, and amlodipine. A single-pill combination of active substances from three recommended groups of antihypertensives in one tablet, an ACE inhibitor, a diuretic, and a calcium channel blocker, allows the product to be universally used in the treatment of hypertension, which facilitates treatment. Krka was the first pharmaceutical company in the world to offer this triple combination to doctors and patients. ( 1 ) We are aware of the importance of preventing cardiovascular events and of the need for new treatment methods for patients with several risk factors. More than half of all people with high blood pressure, for example, also have high cholesterol. When these two risk factors occur together, their impact on disease progression is not only added but multiplied. Therefore, our newest products are single-pill combinations of medications for concurrent treatment of high cholesterol and blood pressure with a single tablet a day. Single-pill combinations of medications that lower lipid and blood pressure help improve patient compliance and thus more effectively prevent occurrences of cardiovascular events. ## Therapeutic equivalence A Krka medication is equal to the originator’s medication. Their pharmaceutical equivalence is demonstrated with in vitro dissolution testing, while in vivo therapeutic equivalence is demonstrated with bioequivalence studies; in both cases we directly compare our medication with the originator’s medication. Krka’s bioequivalence studies are performed in several European and North American countries. They are performed at a high scientific and professional level in line with strict international requirements (Good Clinical Practice (GCP), Good Laboratory Practice (GLP), European Medicines Agency and Food and Drug Administration guidelines) for clinical trials regarding medical, regulatory, and ethical standards. The studies are performed on locations compliant with GCP and GLP, which are regularly inspected by the European and American regulatory authorities. ( 1 ) Krka’s rosuvastatin has a built-in active ingredient that was synthesized using our own synthesis procedure, with the tablet wrapped in an innovative film coating. Therapeutic equivalence with the reference rosuvastatin was proven with a bioequivalence study ( Figure 2 ). ( 3 ) Bioequivalence study of Krka’s rosuvastatin 20 mg versus reference rosuvastatin 20 mg. ## Efficacy and safety in clinical practice After a medication has been launched on the market, we regularly monitor its efficacy and safety in everyday practice by conducting clinical studies. In this way we obtain more in-depth data and give doctors an opportunity to get acquainted with our medications and thus acquire valuable experience. Several international interventional clinical studies have been conducted with our cardiovascular medications, such as INTER-ARS (Atoris), HEMERA (Ampril and Lorista and their single-pill combinations), ROSU-PATH (Roswera), VICTORY (Valsacor and its single-pill combinations) to provide answers to various issues. ( 1 ) The latest, still ongoing study is the PRECIOUS study on Krka’s perindopril single-pill combinations (Dalneva, CoDalneva). Its results are expected in the beginning of 2020. ( 2 ) In non-interventional clinical studies, the patients are monitored in everyday clinical practice, where the selection of patients, treatment method, selection of the medication and its prescribing regimen, study design, and patient monitoring do not differ in any way from the established treatment. ( 1 ) The findings of our clinical studies in almost 350,000 patients in 27 countries demonstrate that Krka’s medications are effective and safe in a wide range of patients. ( 2 ) Study findings are documented, analysed, and presented at international congresses (the clinical study VICTORY was presented at the 26 th Meeting of the European Society of Hypertension (ESH 2016) in Paris and the clinical study ROSUPATH at the congress of the European Society of Cardiology (ESC 2016) in Rome) and published in international medical journals. They contribute to the trust the professional public and patients have had in Krka’s medications for decades. ## Conclusion Our aim is to be a reliable partner in health to doctors, pharmacists, and patients by offering them added-value generic medications developed by our own know-how. This assures high quality of the products and their availability in a wide variety of packaging, strengths, and single-pill combinations. The results of numerous clinical studies show that our medications are effective and well-tolerated in clinical practice.