Zusammenfassung der Merkmale des Arzneimittels - Ursonorm 500 mg Filmtabletten
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Ursonorm 250 mg Hartkapseln Ursonorm 500 mg Filmtabletten |
| Name of the drug substance (INN name): | Ursodeoxycholic acid |
| Pharmaco-therapeutic group (ATC Code): | A05AA02 |
| Pharmaceutical form(s) and strength(s): | Capsules, hard 250 mg Film coated tablets 500 mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/3565/001–002/DC |
| Reference Member State: | Germany |
| Member States concerned: | 500mg: AT, CZ, PL, SK 250mg: BE, BG, CZ, FI, IE, LU,NO, PT, SK |
| Marketing Authorisation Holder (name and address) | Renantos Pharmavertriebsges.mbH Beethovenstraße 10 89340 Leipheim Germany |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | PRO.MED.CS Praha a.s. Telčská 377/1 140 00 Prag 4 Czech Republic |
II.1 Problem statement
For generic application this section is not applicable.
II.2 About the product
Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid present in small quantities in human bile. Exogenously administered UDCA is used as an anticholelithogenic mainly for the dissolution of cholesterol-rich gallstones in patients with functioning gallbladders and in the treatment of primary biliary cirrhosis. The major mechanism by which UDCA achieves bile desaturation is through a decrease in secretion of cholesterol into the bile. UDCA suppresses the synthesis and secretion of cholesterol by the liver and reduces intestinal absorption of cholesterol, but does not inhibit bile acid synthesis. Therefore, bile composition is altered from supersaturated to unsaturated. UDCA also promotes the formation of liquid cholesterol crystal complexes which enhance removal of the cholesterol from the gallbladder into the intestine to be expelled.
UDCA preparations belong to the “preparations for biliary tract and liver therapy” in the ATC classification. The ATC code of ursodeoxycholic acid is A05AA02.
Proposed Clinical Use:
Ursonorm 250 mg Hartkapseln (capsules, hard):
– For dissolution of cholesterol gallstones in the gall bladder. The gallstones must not produce any shadows on the radiograph and should not be of a greater diameter than 15 mm, and the gall bladder, despite the gallstone(s), must be functioning.
– For treatment of gall reflux gastritis.
– For symptomatic treatment of primary biliary cholangitis (PBC), as long as there is no decompensated cirrhosis of the liver.
– Children and adolescents: For treatment of hepatobiliary disease associated with cystic fibrosis in children aged 6 to 18 years.
Ursonorm 500 mg Filmtabletten (film-coated tablets):
– For dissolution of cholesterol gallstones in the gall bladder. The gallstones must not produce any shadows on the radiograph and should not be of a greater diameter than 15 mm, and the gall bladder, despite the gallstone(s), must be functioning.
– For symptomatic treatment of primary biliary cholangitis (PBC), as long as there is no decompensated cirrhosis of the liver.
– Children and adolescents: For treatment of hepatobiliary disease associated with cystic fibrosis in children aged 6 to 18 years.
Ursonorm 250 mg Hartkapseln (capsules, hard):
The product was developed by PRO.MED.CS Praha a.s., as a generic equivalent to the originator product Ursofalk®, adopting the same pharmaceutical form and qualitative composition except for differences in excipients. Excipients for PRO.MED’s formulation were chosen to develop a stable immediate release formulation matching the reference product, both in vivo and in vitro.
Ursonorm 500 mg Filmtabletten (film-coated tablets):
The product was developed by PRO.MED.CS Praha a.s., as a generic equivalent to the originator product Ursofalk® 500 mg film-coated tablets from the German market, adopting the same pharmaceutical form and containing the same concentration of active substance. Excipients for PRO.MED’s formulation were chosen to develop a stable immediate release formulation with similarity in bioavailability of drug substances in comparison with the reference product, both in vivo and in vitro.
II.3 General comments on the submitted dossier
The active substance is not considered a new active substance.
This decentralised procedure concerns an application made under reference to Article 10(1) of the Directive 2001/83/EC for Ursodeoxycholic acid under the trade name Ursonorm 250 mg Hartkapseln (capsules, hard) and Ursonorm 500 mg Filmtabletten (film coated tablets).
The originator medicinal product is Ursofalk 250 mg capsules, hard, registered in Germany since 15.03.1999.
For the 250mg strength, the reference medicinal product in submitted bioequivalence study UDA-BESD-01-PMD/09 is Ursofalk 250 mg capsules, hard, from the Czech market (registered in the Czech Republic since 24th July 1992) and in bioequivalence study UDA-BESD-11-PMD/15, the reference product is the originator Ursofalk 250 mg capsules, hard, from the German market.
For the 500mg strength, the reference product is Ursofalk 500 mg film coated tablets, registered in Germany since 12.05.2006.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles
GMP
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
Copies of written confirmation of the drug product manufacturer, that the drug substance manufacturers operate in compliance with the detailed guidelines on good manufacturing practice for starting materials are presented (dated June, 2016).
GLP
The analytical part of the bioequivalence studies were stated to conform to GLP. However, a GCP compliant conduct of the bioanalytical parts of the trials UDA-BESD-10-PMD/12 and UDA-BESD-06-PMD/11 could not be confirmed (see below).
GCP
The clinical parts of studies UDA-BESD-01-PMD/09 (250mg), UDA-BESD-10-PMD/12 (250mg) and UDA-BESD-06-PMD/11(500mg) were carried out outside the European Union: A statement on GCP compliance is attached to Module 1.
Studies UDA-BESD-11-PMD/15 (250mg) and UDA-BESD-12-PMD/15 (500mg) have been conducted within the EU. Therefore, no statement on GCP compliance is attached to Module 1
Studies UDA-BESD-10-PMD/12 (250mg) and UDA-BESD-06-PMD/11 (500mg) were not
considered acceptable for the demonstration of bioequivalence since a GCP compliant conduct of the bioanalytical parts of the respective trials could not be confirmed in a GCP inspection. Consequently, the results of these studies are not depicted in this document.
Subsequently, two new bioequivalence studies UDA-BESD-11-PMD/15 (250mg) and UDA-BESD-12-PMD/15 (500mg) were conducted by the applicant. A need for GCP inspection of these latter bioequivalence studies is not considered warranted since they comply with the recommendations outlined in a Scientific Advice Meeting at BfArM with the applicant.
III.1 Quality aspects
This application for marketing authorization refers to Ursonorm 250 mg capsules hard. The active ingredient is Ursodeoxycholic acid.
Ursodeoxycholic acid is well-known active substance described in Ph.Eur. CEPs have been provided from all current drug substance manufacturers.
Viral inactivation potential of the manufacturing process of drug substance has been demonstrated.
Development of the finished product Ursonorm 250 mg capsules, hard by PRO.MED.CS. is performed with the objective to obtain generic equivalent to the reference product Ursofalk 250 mg capsules hard. Manufacturing process is described sufficiently. Hard capsules as immediate release
solid dosage form have been selected and the active substance is known to be stable. Wet granulation method has been chosen because of chemical and physical properties of the drug substance.
The influence of the proposed particle sizes has been discussed. Furthermore, discriminatory power of the proposed dissolution method with and without surfactant has been demonstrated.
Except of the dissolution limit the same limits are proposed for the release and shelf life specifications. Dissolution limit only at release has been re-evaluated and tightened. The limit for dissolution in shelf life specification remains the same. This is acceptable.
Analytical procedures and validation have been adequately described. Detailed description of validation of NIR method has been presented. In case of the method used for purity test in drug product specification comparison has been presented of the results of impurities amount in the drug substance with the amount of impurities in the drug product manufacturing from respective substance under release control. There is no significant difference between the results.
According to the presented stability data proposed shelf life of 36 months with the following storage condition “This medicinal product does not require any special storage conditions” is accepted.
This application for marketing authorization refers to Ursonorm 500 mg film coated tablets. The active ingredient is Ursodeoxycholic acid. The Application for Ursonorm 500 mg film coated tablets is approved provided that satisfactory responses are given to the outstanding points for clarification identified in the manufacturing of the drug product.
Ursodeoxycholic acid is well-known active substance described in Ph.Eur.
Development of the finished product by PRO.MED.CS is performed with the objective to obtain generic equivalent to the reference product Ursofalk 500 mg film coated tablets. Manufacturing process and in-process controls are described sufficiently. Film coated tablets as immediate release solid dosage form has been selected and the active substance is known to be stable. Granulation method has been chosen because of chemical and physical properties of the drug substance, e.g. low solubility. Pharmaceutical development of drug product has been discussed and similarity of test and reference product has been demonstrated. To investigate batch to batch consistency of the product, comparative dissolution profile testing should be undertaken on the first three production batches.
The influence of the proposed particle sizes on dissolution of drug product (in QC dissolution medium) has been discussed and demonstrated via statistical evaluation. In the drug product specification the same limits are proposed for the release and shelf life specifications. Test of subdivision of tablets is included in specification. Analytical procedures and validation have been adequately described.
III.2 Non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of ursodeoxycholic acid are well known. As ursodeoxycholic acid is a widely used, well-known active substance, no further studies are required. An overview based on literature review is thus appropriate.
The nonclinical overview refers to 44 publications and 3 study reports (Irwin test in rats, repeated dose toxicity study in rats and a reproductive toxicity study in rats) up to year 2011. Results of the studies are in line with literature data.
The nonclinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
III.3 Clinical aspects
1) Bioequivalence study UDA-BESD-01-PMD/09 was an open label, two-period, two-sequence, two-way crossover, controlled, randomized, single dose bioequivalence study of UDCA 250 mg PMCS, capsules (test formulation) vs. equal dose of Ursofalk® capsules (reference formulation) in 66 healthy male and female volunteers under fasting conditions.
The analysis of study samples (study code URS/AV/II) was conducted between 14th September 2009 and 12th February 2010. The analytical study was terminated on 20th May 2010.
Results: Study UDA-BESD-01-PMD/09
Table 1a. Pharmacokinetic parameters without baseline correction (nontransformed values; arithmetic
mean ± SD, t max (median, range), LLOQ = 31nmol/L, values <LLOQ set to zero Cmax was calculated including for subject 47 Cmax that occurred at 2h, whereas Cmax at 16h was excluded. For calculation of AUC0–24, the latter was included.
| Treatment | AUC 0–10 nmol.h/l | AUC 0–24 nmol.h/l | AUC 0-∞ nmol.h/l | C max 0–12 nmol/l | t max 0–12 h |
| Test | 16855 ± 3938 | 26441 ± 14260 | 7971 ± 2744 | 2.00 (0.67§ – 4.00) | |
| Reference | 16886 ± 3925 | 24171 ± 8268 | 7010 ± 2446 | 2.00 (0.67§ – 4.00) | |
| *Ratio (90% CI) | 99.85 (96.79 – 103.01) | 105.38 (98.54 – 112.7) | 113.68 (103.94 –124.32) | 0 (-0.25 to +0.18) | |
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | |||||
*ln-transformed values
§ 0.67 h first sample time
The upper limit of the 90-% confidence interval slightly exceeded 125 % if testing was performed with the second atypical concentration maximum of subject 47.
Table 1b. Pharmacokinetic parameters without baseline correction (nontransformed values; arithmetic
mean ± SD, t max (median, range), LLOQ = 31nmol/L, values<LLOQ set to zero Cmax and tmax were calculated including Cmax that occurred at 16h for subject 47.
| Treatment | C max 0–16 nmol/l | t max 0–16 h |
| Test | 8064 ± 2875 | 2.00 (0.67§ – 16.00) |
| Reference | 7010 ± 2446 | 2.00 (0.67§ – 4.00) |
| *Ratio (90% CI) | 114.59 (104.36 –125.82) | 0 (-0.25 to +0.25) |
| C max Maximum plasma concentration t max Time until Cmax is reached | ||
*ln-transformed values
§ 0.67 h first sample time
In a secondary analysis, baseline corrected results were presented. Endogenous levels were reported to be about 50-fold less than levels at peak exposure. Baseline correction did not change the outcome of the study.
Sampling schedule, sampling period and washout period were found not to be adequate for the purpose of this study: Cmax had not been characterised adequately as Tmax was observed in altogether 10 subjects at the first sampling time point. AUC0-inf could not be determined and no information about the extrapolated part of AUC is available due to the fact that the elimination constant could not Ursonorm 250 mg Hartkapseln and Ursonorm 500 mg Filmtabletten
DE/H/3565/001–002/DC Public Assessment Report Page 8/12
be determined. The washout period was considered as not quite sufficient. It should have amounted to at least 5 times the elimination half life; considering that carry over cannot be directly assessed for UDCA, being an endogenous substance.
Moreover, validity of the analytical method was found questionable with a major concern relating to the LLOQ and resulting acceptability of analytical runs. Several reanalyses have been presented within the D106ARD, changing the results only slightly and leaving the conclusions on bioequivalence unchanged. However, these analyses were either incomplete or inadequate, and the major concern was upheld regarding study UDA-BESD-01-PMD/09.
In conclusion, bioequivalence is not considered to have been demonstrated indisputably in study UDA-BESD-01-PMD/09.
2) Bioequivalence study UDA-BESD-11-PMD/15 was an open label, single dose, block randomized, two-period, two sequence, two treatment crossover bioequivalence study of UDCA PMS 250 mg x 2 capsules (Test formulation) vs. Ursofalk® 250 mg x 2 (reference formulation) in 66 (62+4 reserves) healthy, adult, male and female volunteers under fasting conditions.
The clinical part of the study was undertaken between 06 January 2016 to 09 March 2016.
The analysis of study samples (analytical method validation code UDA-BE-LCMSMS-01/16, incl. revisions 1) was conducted between 11 March 2016 to 26 March 2016.
Design, conduct and statistical analyses of the study were found to be adequate and in line with respective EMA guidelines. The method used to analyse unconjugated ursodeoxycholic acid in K2-EDTA human plasma was found to be sufficiently validated and suitable for its intended purpose.
For the bioequivalence assessment, ursodeoxycholic acid pharmacokinetic data obtained from 62 subjects that were found evaluable were statistically analysed.
Table 1: Study UDA-BESD-11-PMD/15: Pharmacokinetic parameters for unconjugated ursodeoxycholic acid (non-transformed values; arithmetic mean ± SD, t max median, range)
(N=62)
| Treatment | AUC 0–72 ng/ml/h | net-AUC 0–72 ng/ml/h | C max (0–24) ng/ml | net-C max (0–24) ng/mL | t max h |
| Test | 32087 ± 14544 | 29635 ± 13289 | 5277 ± 2984 | 5243 ± 2990 | 2.00 (0.50 – 5.00) |
| Reference | 33130 ± 15346 | 30395 ± 13882 | 5142 ± 2852 | 5104 ± 2857 | 2.00 (0.50 – 5.00) |
| *Ratio (90% CI) | 97.459 (89.876 – 105.681) | 98.196 (90.268 – 106.822) | 103.594 (93.702 – 114.530) | 103.723 (93.713 – 114.802) | |
| AUC0–72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | |||||
*ln-transformed values
The 90% confidence intervals of AUC0–72, Cmax, net-AUC0–72 and net-Cmax ratios were inside the accepted bioequivalence range of 80.00–125.00 %.
Based on the results of study UDA-BESD-11-PMD/15, bioequivalence of UDCA PMCS 250 mg capsules (Test) with Ursofalk® capsules (Reference) can be concluded.
1. Bioequivalence study UDA-BESD-12-PMD/15 was an open label, single dose, block randomized, two-period, two sequence, two treatment crossover bioequivalence study of UDCA PMS 500mg film-coated tablets (Test formulation) vs. Ursofalk® 500 mg film-coated tablets (reference formulation) in 44 (40 + 4 reserves) healthy, adult, male and female volunteers under fasting conditions.
The clinical part of the study was undertaken between 22 January 2016 to 09 March 2016.
The analysis of study samples (analytical method validation code UDA-BE-LCMSMS-01/16) was conducted between 28 March 2016 to 12 April 2016.
Design, conduct and statistical analyses of the study were found to be adequate and in line with respective EMA guidelines. The method used to analyse unconjugated ursodeoxycholic acid in K2-EDTA human plasma was found to be sufficiently validated and suitable for its intended purpose.
For the bioequivalence assessment, ursodeoxycholic acid pharmacokinetic data obtained from 40 subjects were statistically analysed.
Table 2: Study UDA-BESD-12-PMD/15: Pharmacokinetic parameters for unconjugated ursodeoxycholic acid (non-transformed values; arithmetic mean ± SD, t max median, range) (N=40)
| Treatment | AUC 0–72 ng/ml/h | net-AUC 0–72 ng/ml/h | C max (0–24) ng/ml | net-C max (0–24) ng/mL | t max h |
| Test | 26912 ± 13960 | 24505 ± 12555 | 3717 ± 1400 | 3683 ± 1398 | 2.50 (0.50 – 18.00) |
| Reference | 25092 ± 12628 | 23101 ± 11712 | 3438 ± 1121 | 3410 ± 1120 | 2.00 (0.25 – 18.00) |
| *Ratio | 105.915 | 104.939 | 106.238 | 106.098 | |
| (90% CI) | (96.888 – 115.783) | (95.753 – 115.007) | (96.078 – 117.473) | (95.896 – 117.386) | |
| AUC0–72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | |||||
*ln-transformed values
The 90% confidence intervals of AUC0–72, Cmax, net-AUC0–72 and net-Cmax ratios were inside the accepted bioequivalence range of 80.00–125.00 %. thus permitting to conclude bioequivalence.
Based on the results of study UDA-BESD-12-PMD/15, bioequivalence of UDCA PMCS 500 mg film-coated tables (Test) with Ursofalk® 500mg film-coated tablets (Reference) can be concluded.
No new studies have been performed and none is required for this type of application.
The bioequivalence studies have raised no new or unexpected safety concerns.
The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
Due to the submission date of the marketing authorisation application (before new pharmacovigilance legislation has come into force ) no RMP was and is requested.
With regard to PSUR submission, the MAH referred to the principles laid down in GVP module VII-Periodic safety update report. The MAH may take into account the following:
In accordance with the revised legislation on pharmacovigilance (Directive 2010/84/EU), thelist of European Union Reference Dates (the EURD list) of PSURs has been established and published by EMA. Marketing authorisation holders shall continuously check the EMA webportal for the DLP and frequency of submission of the next PSUR.
For medicinal products authorized under the legal basis of Article 10(1) or Article 10a ofDirective 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.
A proposed common renewal date of 5 years after the finalisation of the procedure was accepted.
Medicinal product subject to medical prescription.
The user test was performed on the package leaflet for the 250 mg capsule formulation.Although the package leaflets for both strength differ slightly (indications), they are considered sufficiently similar for the user test to be acceptable for both strengths. User testing is considered to be adequate.
Ursodeoxycholic acid is a well-established agent, its efficacy and safety have been demonstrated in clinical trials and post-marketing use.
Based on the results of study UDA-BESD-11-PMD/15, bioequivalence of UDCA PMCS 250 mg capsules (Test) with Ursofalk® capsules (Reference) can be concluded and the benefit risk assessment is positive. Marketing authorization is recommended for Ursonorm 250mg Hartkapseln (capsules, hard).
Based on the results of study UDA-BESD-12-PMD/15, bioequivalence of the applicant’s product UDCA PMCS 500 mg film-coated tablets with equal dose of the reference product Ursofalk® 500 mg film-coated tablets can be concluded and the benefit risk assessment is positive. Marketing authorization is recommended for Ursonorm 500mg Filmtabletten (film-coated tablets).
The application is approved. For intermediate amendments see current product information.