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https://doi.org/10.15836/ccar2024.322

Krka’s Medicines – Generations of Knowledge for Better Health of Patients

Breda Barbič-Žagar orcid id orcid.org/0000-0002-1173-7361 ; Krka, d. d., Novo mesto, Slovenija
Tina Dular-Meglič ; Krka, d. d., Novo mesto, Slovenija
Jana Golob orcid id orcid.org/0009-0004-7230-3462 ; Krka, d. d., Novo mesto, Slovenija
Alenka Kmecl ; Krka, d. d., Novo mesto, Slovenija
Nataša Uranič orcid id orcid.org/0009-0004-7348-2810 ; Krka, d. d., Novo mesto, Slovenija
Saša Žikić orcid id orcid.org/0009-0002-4555-6590 ; Krka, d. d., Novo mesto, Slovenija


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Sažetak

SUMMARY
Trust in the power of knowledge. Reliability in choosing treatment. Loyalty to a mission that prioritizes health above all. These are the values that have been the foundation of Krka for 70 years. Our main purpose is to be a reliable global partner in health for doctors, pharmacists, and patients, while pursuing our mission to develop high-quality, safe, and effective medicines. The importance of the vertically integrated production model has been recently demonstrated. This model allows us to have complete oversight of the entire production process, from the active ingredient to the finished product, ensuring high-quality. Our innovations demonstrate our dedication to the well-being of consumers. In recent years, we have launched several valuable single-pill combinations. These include widely used combinations of antihypertensives, as well as other combinations for which we were pioneers among pharmaceutical producers. Our extensive portfolio of medicines addresses most common diseases, providing healthcare professionals with a variety of treatment options. We are also one of the few generic pharmaceutical companies whose medicines are supported by numerous post-registration clinical studies, demonstrating their effectiveness and safety in clinical practice. For 70 years, we have been committed to the health of current and future generations.

Ključne riječi

high-quality medicines; vertically integrated production; clinical studies

Hrčak ID:

320165

URI

https://hrcak.srce.hr/320165

Datum izdavanja:

22.8.2024.

Podaci na drugim jezicima: hrvatski

Posjeta: 229 *




Introduction

Trust in the power of knowledge. Reliability in choosing treatment. Loyalty to a mission that prioritizes health above all. These are the values that have been the foundation Krka for 70 years. For seven decades now, we have been committed to health. We consistently endeavor to consider people’s needs.

Worldwide presence

Our mission is to enable people to live a healthy life. Our main purpose is to be a reliable global partner in health for doctors, pharmacists and patients. Our medicines, originating from our parent company in Slovenia, have reached far and wide. We have established manufacturing facilities in various parts of Europe, all maintaining the same quality standards. Our medical representatives share information about our medicines and the latest treatment guidelines with healthcare professionals in over 40 markets worldwide, supporting them in solving medical issues. Today, more than 100 million people in over 70 countries are being treated with our products. Among these, the most important product group are prescription pharmaceuticals. (1)

Wide variety of medicines against most common diseases

For decades, cardiovascular diseases (CVDs) have been the leading cause of mortality and a major contributor to disability. In 2021, 20.5 million people died from a cardiovascular (CV) condition, a figure that accounted for around one-third of all global deaths. (2) Efforts are being made to investigate ways to optimally manage risk factors for CVD and to improve medical interventions reducing the clinical burden associated with the development of the disease. High blood pressure (BP) and high levels of blood lipids are two of the most commonly co-occurring CV risk factors, as they are often present in the same individuals. (3) This was evident in the recently published results of the DISCOVERY epidemiological study, where 54% of patients had both diseases. This was prospective study investigating the management of arterial hypertension (AH) and/or hypercholesterolemia (HCL) in real-world clinical practice between 2021 and 2022 in a cluster of South-Eastern European countries with high or very-high risk. (4,5) Patients were observed over the course of 12 weeks, with data recorded at two time points. The collected data reflect the current situation regarding adherence to guidelines in the management of both diseases in regular clinical practice. Overall, among all patients with AH and HCL, only 4.7% reached the target BP level and LDL-cholesterol (LDL-C) goals as defined by guidelines (Figure 1). (4,6,7)

FIGURE 1 Reaching target BP levels among patients with AH, LDL-C goals among patients with HCL, and target levels (defined by the guidelines) for both BP and LDL-C among patients with both diseases. BP – blood pressure; AH – arterial hypertension; LDL-C – LDL cholesterol; HCL – hypercholesterolemia; ESC/EAS – European Society of Cardiology/European Atherosclerosis Society
CC202419_7-8_322-7-f1

At Krka, we closely monitor most common diseases and offer a wide portfolio of medicines to address them. We take pride in providing 1,000 products for most common diseases of our time. Every day, we offer a variety of solutions for individuals with hypertension. Angiotensin-converting enzyme inhibitors (ACE inhibitors) and sartans are two of the most important classes of antihypertensives in our current portfolio. Regarding ACE inhibitors, we provide the most comprehensive perindopril-based product range in Europe, from monotherapy to a range of double or triple single-pill combinations (SPC) and SPCs with statins. Additionally, we offer many sartan-based products, including valsartan, losartan, and telmisartan. The sartan product portfolio includes sartan-based SPCs with a diuretic and a calcium channel blocker. (1) For individuals at increased CVD risk, our portfolio consists of two high-intensity statins, atorvastatin and rosuvastatin, aiming for at least a 50% reduction in LDL-C. We also offer an SPC containing rosuvastatin and ezetimibe (Co-Roswera®). (1) In addition to these medicines, Krka is entering a new therapeutic area with anticoagulant medicines with Xerdoxo® (rivaroxaban), one of the most advanced anticoagulants, and Daxanlo® (dabigatran). (1) Furthermore, we provide options for glycemic control for a broad spectrum of diabetic patients with Maysiglu® (sitagliptin, a dipeptidyl peptidase-4 inhibitor) or its SPC Maymetsi® (sitagliptin/metformin). (1)

High-quality-assured reliable medicines

Our mission is to develop high-quality, safe, and effective medicines and to make no compromises in this regard. We are committed to continuous investments in development and research and committed to state-of-the-art technology, equipment, and processes. We are also committed to innovation, which we incorporate into all our operations. Numerous laboratory tests and analyses ensure comprehensive quality control. Our skilled and dedicated teams are devoted to their work, and their final clients, the patients.

Recently, it has been demonstrated how important our vertically integrated production model is, as it allows the company to have complete oversight of the entire production process, from the active ingredient to the finished product. This results in high quality with no surprises. In Europe, several producers of medicines containing valsartan, losartan, and irbesartan had to withdraw their products from the market due to nitrosamine impurities. After an in-depth analysis, the European Medicines Agency set limits on maximum levels of nitrosamine impurity levels in sartan-containing products with the goal of achieving no quantifiable impurities in the future. (8) In 2021, information emerged about potentially mutagenic azido impurities in certain sartan-containing products. As a result, the European Directorate for the Quality of Medicines (EDQM) required producers to recall their products and take appropriate actions to ensure that the level of azido impurities was below the threshold levels. (9,10) Our valsartan medicines were not affected by these measures because the scientifically evaluated synthesis routes of the sartan active ingredients prevented the formation of nitrosamine impurities. Due to the absence of any quantifiable levels of nitrosamine and azido impurities (which were detected only in traces, significantly below the permissible limit), our valsartans have remained available to patients without restriction since their launch. (11,12) Several of Krka’s medicines, including our valsartan, have obtained a Certificate of Suitability issued by the EDQM, which represents the highest quality standard in Europe. (11,13,14)

Award-winning innovations demonstrate our dedication to the well-being of consumers. Our experts continuously seek new solutions to make treatment easier and improve adherence, which in turn enhances therapeutic outcomes. In recent years, Krka has launched several valuable SPCs, including widely used combinations of ACE inhibitors or sartans with diuretics or amlodipine, as well as triple combinations with both. We also offer combinations of statins and ezetimibe, which are crucial for providing intensive oral lipid-lowering therapies to many patients at increased CV risk. Our portfolio includes combinations for which we were pioneers among pharmaceutical producers, such as the rosuvastatin/perindopril/indapamide combination (Roxiper®) for the concomitant treatment of AH and HCL available in Croatia.

Optimized production processes have not only increased our production capacity but also improved the quality of active substances and reduced hazardous waste. This reduces our negative impact on the environment and ensures a sustainable future. In dialogue with experts, we continually seek solutions with people and the environment in mind. These efforts resulted in our first ESG sustainability rating in 2023, positioning us among the top 10% of pharmaceutical companies worldwide. (1)

Demonstrating clinical efficacy

The effectiveness and efficacy of our medicines are clinically proven – we support you in your confident approach to clinical practice. Krka is one of the few generic pharmaceutical companies whose medicines are supported by a large number of post-registration clinical studies. After a medicine is launched on the market, its efficacy and safety are monitored in everyday practice through clinical studies, providing more in-depth knowledge and familiarity with the company’s medicines. Several international interventional clinical studies have been conducted with our medicines, including INTER-ARS (Atoris®) (15), HEMERA (Ampril® and Lorista® and their single-pill combinations) (16), ROSU-PATH (Roswera®) (17), VICTORY (Valsacor® and its single-pill combinations) (18) and PRECIOUS (Dalneva® and Co-Dalneva®). (19,20) These clinical trials contribute to scientific achievements, are scientifically justified, and are conducted in compliance with applicable legal requirements, good practice guidelines, and ethical standards. Therefore, the data obtained from these clinical trials are credible and accurate. Additionally, numerous non-interventional clinical studies, monitoring patients in regular clinical practice and following established treatments, have been conducted with our medicines. The latest ongoing study is the DIVERSITY study on Krka’s sitagliptin and its SPC with metformin in various groups of type 2 diabetic patients. The interim analysis of the DIVERSITY study demonstrated a statistically significant reduction in hemoglobin A1c, fasting plasma glucose, and postprandial glucose after six months of treatment. Both medicines were generally well-tolerated, without a significant risk of hypoglycemia. Furthermore, despite the majority of patients with comorbidities having AH, adding sitagliptin or sitagliptin/metformin SPC did not appear to increase the risk of CV complications.

The efficacy and safety of our medicines have been demonstrated in a wide range of patients, in over 150 clinical studies, and involving nearly 350,000 patients from 27 countries. (1) Therefore, the results of these clinical studies are one of the key added values of Krka’s medicines, contributing to accurate and reliable decisions in everyday patient care.

Conclusion

For 70 years, we have been committed to the health of current and future generations. On this anniversary, our greatest wish is to remain your reliable partner. We will continue to work together with you to fulfil our common mission: living a healthy life.

LITERATURE

1 

Annual report 2023. Krka, d. d., Novo mesto, 2024. [cited 2024 June 18]. Available from:http://www.krka.biz/en/

2 

Di Cesare M, Bixby H, Gaziano T, Hadeed L, Kabudula C, McGhie DV, et al. World Heart Report 2023: Confronting the World’s Number One Killer. Geneva, Switzerland. World Heart Federation. 2023 [cited 2024 June 18]. Available from:https://world-heart-federation.org/resource/world-heart-report-2023/

3 

Perrone V, Veronesi C, Gambera M, Nati G, Perone F, Tagliabue PF, et al. Treatment with Free Triple Combination Therapy of Atorvastatin, Perindopril, Amlodipine in Hypertensive Patients: A Real-World Population Study in Italy. High Blood Press Cardiovasc Prev. 2019 October;26(5):399–404. https://doi.org/10.1007/s40292-019-00336-2 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/31463886

4 

Statistical analysis report. International real-world study exploring the management of arterial hypertension and hypercholesterolemia. Data on file. Krka d. d., Novo mesto, Slovenia. 2023

5 

Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). Eur Heart J. 2021 September 7;42(34):3227–337. https://doi.org/10.1093/eurheartj/ehab484 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/34458905

6 

Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J. 2018 September 1;39(33):3021–104. https://doi.org/10.1093/eurheartj/ehy339 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/30165516

7 

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020 January 1;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/31504418

8 

Sartan medicines: companies to review manufacturing processes to avoid presence of nitrosamine impurities. European medicine agency. 2019 [cited 2024 June 18]. Available from:https://www.ema.europa.eu/en/news/sartan-medicines-companies-review-manufacturing-processes-avoid-presence-nitrosamine-impurities

9 

Risk of presence of mutagenic azido impurities in sartan active substances with a tetrazole ring. European Directorate for the Quality of Medicines & HealthCare. 2021 [cited 2024 June 18]. Available from:https://www.edqm.eu/en/-/risk-of-presence-of-mutagenic-azido-impurities-in-sartan-active-substances-with-a-tetrazole-ring

10 

Risk of the presence of mutagenic azido impurities in losartan active substance. European Directorate for the Quality of Medicines & HealthCare. 2021 [cited 2024 June 18]. Available from:https://www.edqm.eu/en/-/risk-of-the-presence-of-mutagenic-azido-impurities-in-losartan-active-substance

11 

Grošelj M, Barbič-Žagar B. Krka’s Added-value Generic Medications. Cardiol Croat. 2019;14(5-6):146–9. https://doi.org/10.15836/ccar2019.146

12 

Krka’s sartans not affected by the recalls due to azido impurities. Krka website. 2021 [cited 2024 June 18]. Available from:https://www.krka.biz/en/media-centre/news/krkas-sartans-not-affected-by-the-recalls-due-to-azido-impurities/12514/

13 

Certfication EDQM. EDQM [cited 2024 June 18]. Available from:https://extranet.edqm.eu/publications/recherches_CEP.shtml

14 

Marinšek G, Glavač Povhe A, Milovanovič Jarh D, Barbič-Žagar B. High-quality Valsartans Contributing to the Treatment of Hypertension and Beyond for More than 15 Years. Cardiol Croat. 2022;17(7-8):134–9. https://doi.org/10.15836/ccar2022.134

15 

Boh M, Opolski G, Poloński L, Zambrzycki J, Poredos P, Ceska R. Porównanie skuteczności i bezpieczeństwa stosowania atorwastatyny generycznej i referencyjnej u osób zwiększonego ryzyka wieńcowego z hiperlipidemią. Kardiologia po Dyplomie. Wydanie Specjalne. 2006;3-9.

16 

Chazova IE, Martyniuk TV. [Possibilities of rational combination antihypertensive therapy: results of HEMERA international clinical trial]. Ter Arkh. 2013;85(10):10-22. Russian. PubMed:https://pubmed.ncbi.nlm.nih.gov/24437213/

17 

Cevc M, Dan GA, Karadi I, Lutai M, Reiner Z, Shlyakhto E, et al. The efficacy and safety of rosuvastatin in a wide population of patients with hyperlipidemia and the placement of additional strengths of 15 mg and 30 mg in clinical practice. The ROSU-PATH trial: international, randomized, open-label, prospective trial. Krka website. 2021 [cited 2024 June 18]. Available from:https://www.krka.biz/en/for-professional-public/kmf/prescription-pharmaceuticals/cardiovascular-diseases/rosupath/

18 

Accetto R, Chazova IY, Sirenko Y, Vincelj J, Widimsky J Jr, Barbič-Žagar B. The efficacy and safety of valsartan and combination of valsartan and hydrochlorothiazide in the treatment of patients with mild to moderate arterial hypertension – the VICTORY trial. Kardiol Pol. 2017 January;75(1):55–64. https://doi.org/10.5603/KP.a2016.0135 PubMed: http://www.ncbi.nlm.nih.gov/pubmed/27714718

19 

Brguljan J, Chazova I, Gaciong Z, Simic D, Vajer P, Zelveian, et al. Effect of single pill combinations on central systolic blood pressure. J Hypertens. 2022 June;40 Suppl 1:e304. https://doi.org/10.1097/01.hjh.0000838696.92081.37

20 

Brguljan J, Chazova IE, Gaciong Z, Simic D, Vajer P, Zelveian PH, et al. Single-pill combination enables fast target BP achievement. J Hypertens. 2023 January;41 Suppl 1:e394–5. https://doi.org/10.1097/01.hjh.0000916860.25615.9f


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