Our medicines are produced in a variety of dosage forms: tablets, capsules, ampoules, etc. We develop new dosage forms that facilitate administration and enable new ways of usage.

An important milestone was the development of the sustained-release dosage form. This innovation is the result of our own know-how, for which we also obtained a European patent. Sustained-release tablets provide reduction in plasma level fluctuation maintenance of constant active ingredient levels over a longer period of time, which consequently leads to fewer adverse reactions and better tolerability, just once-a-day dosing, and improved patient compliance, which in turn results in fewer costs for the health care system; (1) Krka’s gliclazide (Gliclada^®) is available in this dosage form (Figure 1).

Multilayer tablets allow several incompatible active ingredients to be joined together into a single dosage unit. They are built into different layers that release the active ingredient at different intervals and speeds. This guarantees that active ingredients remain chemically stable and that the product’s quality is adequately sustained. At the same time it allows the number of tablets to be reduced, which in turn improves patient adherence and treatment outcome. An example of this innovation, for which Krka was awarded the Golden Award for innovation by the Chamber of Commerce and Industry of Slovenia, are bilayer tablets containing telmisartan and hydrochlorothiazide (Tolucombi^®), which act synergistically on blood pressure (Figure 2). (1)

By offering innovative strengths and various fixed-dose combinations we allow physicians to select the most appropriate medicine for their patients. We were the first company to launch 30 mg and 60 mg strengths of atorvastatin (Atoris^®) and 15 mg and 30 mg strengths of rosuvastatin (Roswera^®). The fixed-dose combination of an antihypertensive and a statin (Atordapin^®) contains amlodipine and atorvastatin as the two active ingredients, which allows doctors to treat two diseases, hypertension and hyperlipidemia, with just one tablet. An outstanding range of almost 60 fixed-dose combinations of different antihypertensives in different strengths allows doctors to select the optimal treatment for any patient with arterial hypertension. (1) We were the first generic producer in Europe to introduce perindopril/amlodipine (Dalneva^®) and many other fixed-dose combinations.

A generic medicine is therapeutically equivalent to the reference medicine when bioequivalence is established and until it is scientifically proven that there is a substantial difference between the two in terms of safety and efficacy. The concept of bioequivalence is based on bioavailability, which is defined by the rate and extent of the active ingredient’s absorption from the site of application to the central blood stream. It is based on comparing the pharmacokinetic profiles of the active ingredient in the plasma (comparison of the maximum concentration of the active ingredient in the plasma that defines the rate and extent of the active ingredient’s absorption in the central bloodstream, and the area under the curve of the active ingredient’s plasma concentrations which defines the extent of absorption). Bioequivalence is based on the 90-percent confidence interval for the ratio of select bioavailability parameters that needs to lie in the 0.80–1.25 interval, or 0.75–1.33 in exceptional cases. (3, 4)

Krka’s bioequivalence studies are performed in various European and North American countries. They are performed on a high scientific and professional level in line with strict international requirements (Good Clinical Practice – GCP, Good Laboratory Practice – GLP, European Medicines Agency, Food and Drug Administration) for clinical trials considering 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)

The therapeutic equivalence of perindopril (Perineva^®) in the dose of 8 mg compared with the reference medicine in the dose of 10 mg was demonstrated with a bioequivalence study on 36 healthy volunteers, who received a single dose of the medicine under fasting conditions (Figure 3). (5)

After the medicine has been launched to the market its efficacy and safety are regularly verified and confirmed in everyday practice with clinical studies. In this way, more in-depth data are obtained and physicians gain an opportunity to get even more acquainted with our medicines and thus acquire valuable experience. Over the years various clinical studies have been performed: international interventional clinical studies such as INTER-ARS and ATOP (Atoris^®), ROSU-PATH (Roswera^®), HEMERA (Ampril^® and Lorista^® and their fixed-dose combinations with hydrochlorothiazide, Tenox^®), and VICTORY (Valsacor^® and its fixed-dose combinations with hydrochlorothiazide), where various issues beyond the established treatment were analyzed, and non-interventional clinical studies where patients in everyday clinical practice were monitored and where the selection of patients, treatment method, selection of the medicine and its prescribing regimen, study design, and patient monitoring did not differ in any way from the established treatment. (1)

All clinical studies are conducted in compliance with Good Clinical Practice. This assures the protection of subjects involved in the studies (their rights, safety, well-being) and the quality, reliability, and integrity of data collected. (6) Interventional clinical studies with Krka‘s medicines conducted in the European Union are applied also in the European Clinical Trials Database. This assures the transparency of the clinical studies data and effective supervision of the conduct of the clinical study. (7)

Among generic pharmaceutical companies, the largest number of post-authorization clinical studies has been conducted with our key products from different therapeutic areas. So far over 270,000 patients in 27 countries have been included in more than 120 clinical studies with Krka’s medicines; of these more than 114,000 patients were treated with cardiovascular medicines. (8) The results from these studies demonstrate that our medicines are effective and safe in a wide range of patients. The study results are documented, analyzed, and published in international medical journals, and contribute to the trust the professional public and patients have had in Krka’s medicines for decades. (1)

Krka’s value-added cardiovascular medicines are developed using the company’s own know-how and allow therapy optimization with new dosage forms and treatment options. Their equivalence to the originator's product is demonstrated by in vivo bioequivalence studies. The results of numerous clinical studies show that they are effective and well tolerated by patients in real clinical practice.