Tillhepo 250 mg Hartkapseln - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete - Tillhepo 250 mg Hartkapseln

TABLE OF CONTENTS

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product(s) in the RMS	Nuzavi 250 mg/ 500mg Hartkapseln
Name of the drug substance (INN name):	Ursodeoxycholic acid
Pharmaco-therapeutic group (ATC Code):	A05AA02
Pharmaceutical form(s) and strength(s):	Capsule, hard; 250 mg, 500mg
Reference Number(s) for the Decentralised Procedure	DE/H/5186/001–002/DC
Reference Member State:	DE
Member States concerned:	FR
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Marketing Authorisation Holder (name and address)	Tillotts Pharma GmbH Warmbacher Straße 80 79618 Rheinfelden Germany
Names and addresses of all manufacturer(s) responsible for batch release in the EEA	ABC Farmaceutici S.p.A Canton Moretti, 29 Loc.S. Bernardo 10015 Ivrea Italy

INTRODUCTION

Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for Nuzavi 250mg / 500mg Hartkapseln, in the treatment of adults

for the dissolution of cholesterol gallstones in the gall bladder in adults. The gallstones

should be X-ray negative and have a diameter less than 15 mm. The gall bladder must be functioning despite the gallstone(s)

for Primary biliary cholangitis (PBC) stages I – III

and in the treatment of the paediatric population

for hepatobiliar disorder associated with cystic fibrosis in children and adolescents (aged 6 to

less than 18 years),

is approved

provided that the applicant commits to perform a number of post authorisation follow- up measures to be reported back to the Member States within predefined timeframes.

A preliminary list of such follow-up measures are in section V of this report.

Based on the submitted dossier, a need for inspection of the submitted BE study USO-P1–498 is currently not considered warranted.

There is no need for involvement of PRAC.

II. EXECUTIVE SUMMARY

II.1 Problem statement

N/A for a generic application.

II.2 About the product

Ursodeoxycholic acid (UDCA), the 7-β-epimer of the primary bile acid chenodeoxycholic acid (CDCA), 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. It is furthermore used in the treatment of primary biliary cholangitis, as well as more recently in the treatment of hepatobilliary disorders associated with cystic fibrosis (CFAHD) in children aged 6 to less than 18 years.

The major mechanism by which UDCA is thought to achieve bile desaturation is through a decrease of the cholesterol content of bile and bile stones by reducing hepatic secretion of cholesterol and the fractional reabsorption by the intestines. This leads to bile composition being 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.

In treatment of patients with primary biliary cholangitis several different mechanisms have been shown. A change in the composition of the bile with a reduction of toxic, endogenous, mainly lipophilic bile acids and an increase in ursodeoxycholic acid are considered to be of largest importance. In addition the flow of bile is stimulated, which results in a faster conversion of the bile acids. The intestinal post-absorption of e.g. cholic acid and other bile acid metabolites are reduced. In vitro ursodeoxycholic acid also has a direct protective effect on hepatocytes.

Paediatric population:

Cystic fibrosis

There is evidence that treatment with ursodeoxycholic acid can decrease bile duct proliferation, halt progression of histological damage and even reverse hepato-biliary changes if given at early stage of CFAHD. Treatment with ursodeoxycholic acid should be started as soon as the diagnosis of CFAHD is made in order to optimize treatment effectiveness.

UDCA preparations belong to the “preparations for biliary tract and liver therapy” in the ATC classification. The ATC code of ursodeoxycholic acid is A05AA02.

The claimed indication and the posology are the same as for the reference medicinal product and read as follows:

Nuzavi is indicated in adults for:

– The dissolution of cholesterol gallstones in the gall bladder. The gallstones should be X-ray negative and have a diameter less than 15 mm. The gall bladder must be functioning despite the gallstone(s).

The daily dose depends on body weight and ranges from 8 – 12 mg/kg body weight a day to be taken in the evening.

– Primary biliary cholangitis (PBC) stages I – III.

The daily dose depends on body weight, and ranges from 12–16 mg kg of body weight.

Paediatric population:

Hepatobiliar disorder associated with cystic fibrosis in children and adolescents (aged 6 to less than 18 years).

The recommended dose is 20 mg/kg/day in 2–3 divided doses, with a further increase to 30 mg/kg/day if necessary.

Of note, the pharmaceutical forms of both strengths of Nuzavi are indivisible capsules, unlike the originator’s 500mg strength, which is a film-coated tablet that can be divided into equal doses of 250 mg each to provide all recommended body weight dependent dosages in all three indications. Since there are at present no standards or regulatory requirements in the EU that specifically address scoring of tablets, this difference in scoring will have to be accepted, although consistent scoring would be considered preferable.

In consequence, whereas all recommended doses can be achieved with both strengths of the originator as well as Nuzavi 250 mg hard capsules, only few of the recommended body weight dependent doses will be achievable with only the higher strength Nuzavi 500mg by itself in all three indications applied for. Prescription of the higher strength Nuzavi 500mg will therefore have to be combined with the additional co-prescription of the lower strength Nuzavi 250mg for the vast majority of patients in all three indications applied for. In the RMS, this will deviate from common practice, since at present all authorised 500 mg formulations of ursodeoxycholic acid are divisible film-coated tablets. According to the Applicant, medication errors resulting in significant under- or overdosing will not create an unacceptable risk in view of patient safety, based on the overdose information available on Ursodeoxycholic acid. Yet, readability user testing for the proposed package leaflets of Nuzavi executed during the procedure had a negative outcome. Commitment has been given by the Applicant to execute second readability user testing for amended Nuzavi 250mg and Nuzavi 500mg package leaflets after closure of the procedure to be submitted via variation procedure to demonstrate that the package leaflets are legible, clear and easy to use. The Applicant further committed not to launch Nuzavi 250mg and Nuzavi 500mg prior to approval of this variation. Since the submitted Risk Management Plan, version 1.1 signed 11 December 2017, was considered acceptable provided that it is updated with the finally adopted product information wording, the Applicant’s commitment is listed as post-authorisation follow-up measure to be reported back to the RMS and CMS within predefined timeframe pursuant to Article 21a. In addition the Applicant committed to change the color of Nuzavi 250mg via post-approval variation procedure to reduce the risk of medication errors and to not launch Nuzavi 250mg and Nuzavi 500mg prior to approval also of this variation and there are also other commitments.

II.3

General comments on the submitted dossier

This decentralised application concerns a generic version of URSODEOXYCHOLIC ACID, under 2 trade names. In this Assessment Report, the name Nuzavi 250 mg/ 500 mg Hartkapseln or simply UDCA 250 mg/500mg capsules is used. The legal basis for this application is Article 10(1) of Directive 2001/ 83/EC. With GERMANY as the Reference Member State in this Decentralized Procedure, Tillotts Pharma GmbH, Warmbacher Strasse 80, 79618 Rheinfelden, Germany is applying for the Marketing Authorisations for Nuzavi 250 mg/ 500 mg Hartkapseln in FRANCE.

The originator product is Ursofalk 250mg Kapseln, capsules, hard, by Dr. Falk Pharma GmbH, Leinenweberstr. 5, 79108 Freiburg im Breisgau, Germany, registered since 03–15–1999 in Germany (MA-No. 39200.00.00). The reference for higher strength Nuzavi 500mg Hartkapseln is Ursofalk 500mg film-coated tablet by Dr. Falk Pharma GmbH, authorised since 12–05–2006 in Germany (MANo. 54690.00.00).

In the bioequivalence study, the reference Ursofalk 250mg capsules was sourced from Norway.

The clinical dossier contains two study reports: one report of a bioequivalence study and one bioanalytical study report, including a method validation report. This is considered adequate for a generic application.

General principles outlined in the Note for Guidance on the investigation of bioequivalence (CPMP/QWP/EWP/1401/98 Rev. 1/Corr*) and in the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**) have generally been followed, although suitability of a reference and two internal standards used for bioanalysis of study samples still needs to be documented via post-approval variation procedure as committed by the Applicant.

No scientific advice was given for this product.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.

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.

GMP active substance

Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

GLP

In line with the type of application procedure no non-clinical studies have been performed.

GCP

A statement on the application of appropriate GCP standards in the submitted study USO-P1–498 has been provided. During assessment no issue of GCP non-compliance arose.

Based on the submitted dossier, a need for inspection of the submitted BE study USO-P1–498 is currently not considered warranted.

III. SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance

Ursodeoxycholic acid is well-known active substance described in Ph.Eur.. A valid CEP has been provided. A copy of the CEP is presented in the documentation. Additional tests to the requirements stated in the EP monograph are added to the CEP (Test for residual solvents by gas chromatography). Presented drug substance specifications from the drug substance and the drug product manufacturer comply with the current Ph.Eur. monograph.

Drug Product

Proposed drug product is a white capsule, for the 250 mg strength the capsule size 0, for the 500 mg the capsule size 00. The excipients used are maize starch, silica colloidal anhydrous and magnesium stearate. All excipients used in the formulation are well known and also present in the reference product. All the excipients comply with the relevant European Pharmacopoeia monographs. Pharmaceutical development has been described in detail. Ursodeoxycholic acid is practically insoluble in acidic solutions. The dissolution tests were evaluated at pH 6.8, 7.5 and 8.4 media.

Dissolution method has been switched from in-house method to the British Pharmacopeia. This approach is considered acceptable. In general proposed dissolution method and dissolution limit is acceptable.

Manufacturing process of drug product is a standard process. The primary packaging material is a transparent PVC/Aluminium blister. Critical steps have been identified and in-process controls have been described. Proposed drug product specification is adequate to control quality of drug product. Due to the high stability of the drug substance and the fact that no degradation has been noted in the stability testing done on the drug product, a shelf-life of 5 years is proposed for UDCA 250 mg and UDCA 500 mg capsules without any special storage conditions.

In view to pharmaceutical quality the medicinal product is recommended for approval.

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, the applicant has not provided additional studies and further studies are not required. The overview based on literature review is thus appropriate.

The non-clinical overview is dated December 2017. In response to a request the non-clinical has been actualised in order to cover the topics impurities and excipients in the medicinal product under review and to include more recent scientific literature. The report refers to 88 publications up to year 2017.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA)

Since Nuzavi is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

III.3 Clinical aspects

Pharmacokinetics

To support the application, the applicant has submitted as report one of bioequivalence studies (USO-P1–498).

The study was a single center, randomized, single dose, laboratory-blinded, 2-period, 2-sequence, crossover study to evaluate and compare the relative bioavailability and therefore the bioequivalence of two different formulations of ursodeoxycholic acid in 48 healthy volunteers after a single oral dose administration of 500 mg (2 × 250 mg) under fasting conditions with a wash-out of 28 days.

Regarding the strength to be investigated, it is difficult to draw firm conclusions regarding doselinearity of the low solubility drug UDCA based on the published literature. At doses above 300 mg there seems to be a less than proportional increase in AUC with increasing dose; however, the degree of non-linearity did not seem very pronounced. UDCA is an endogenous substance and use of a dose of 2×250 mg instead of 1×250 mg in bioequivalence study USO-P1–498 has been considered acceptable for the 250mg strength for the reasons that (i) multiple doses of 250mg have been administered also in other bioequivalence studies in various European procedures to enable reliable determination of the concentrations above baseline, and (ii) the point estimates in study USO-P1–498 were close to 100% with relatively low variability observed. Regarding the higher strength, a bioequivalence study with the 500mg strength would differ only in that the dose would be presented in one capsule instead of two capsules, since the two strengths are made from one common blend. Considering that the point estimates in study USO-P1–498 were close to 100% with relatively low variability observed this difference may be safely assumed to be negligible.

Conduct and statistical analyses of the study were found to be adequate and in line with respective EMA guidelines, except that AUC(0–72h) still needs to be reported via post-approval variation procedure as committed by the Applicant (see section VI) since AUCinf and %AUCextrapol could not be determined. The sampling period of –24 to 72 hours was adequate for the immediate release product to enable baseline correction. Frequent early sampling adequately covered the absorption process. The washout of 28 days was somewhat shorter than 5 times the elimination half- life of UDCA, i.e. 29 days.

A validated method involving a surrogate matrix approach for calibrants was used to analyse UDCA, glyco-UDCA and tauro-UDCA in human plasma. Suitability of use of a reference standard and two internal standards past their expiry date still needs to be fully documented via post-approval variation procedure as committed by the Applicant.

Subject- and period-specific baseline correction was done which is adequate since UDCA is an endogenous substance.

Pharmacokinetic parameters were determined for unconjugated UDCA with and without baseline correction and additionally for total UDCA with and without baseline correction. Total UDCA levels were determined by the summation of the unconjugated and both conjugated UDCA levels as well as adjusted based on the molecular weight of the unconjugated UDCA.

Results on the main pharmacokinetic parameters are given in the following tables:

Table 1a. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max

median, range) for Unconjugated Ursodeoxycholic acid-Baseline Uncorrected in study USO-P1–498

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	22068.8 (11502.2)	NC	5052.1 (1990.8)	2.50 (0.67, 5.00)
Reference	22382.0 (13176.4)	NC	4996.4 (2023.7)	2.00 (1.00, 5.00)
*Ratio (90% CI)*	100.58 (93.19 – 108.55)		101.86 (93.65 – 110.78)
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 NC=Not Calculable

The intra-subject coefficient of variation was 23.4% and 20.7% for Cmax and AUCT, respectively.

For almost all subjects, the terminal phase of UDCA could not be adequately estimated and the elimination parameters (AUC∞, AUCT/∞, Kel and T½el) were non-evaluable for all subjects.

Tmax did not occur at the first sampling point in any of the subjects.

Table 1b. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD,

tmax median, range) for Unconjugated UDCA-Baseline Corrected in study USO-P1–498

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	21747.7 (11047.4)	NC	5047.8 (1988.2)	2.50 (0.67, 5.00)
Reference	21903.5 (12414.0)	NC	4990.1 (2019.0)	2.00 (1.00, 5.00)
*Ratio (90% CI)	100.94 (93.55 – 108.92)		101.90 (93.69 – 110.83)
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

The intra-subject coefficient of variation was 23.4% and 20.6% for Cmax and AUCT, respectively.

Again, the terminal phase of UDCA could not be adequately estimated for almost all subjects. Tmax did not occur at the first sampling point in any of the subjects.

Table 2a. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD,

tmax median, range) for Baseline Uncorrected Total UDCA in USOP1–498

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	59751.8 (21616.0)	NC	5569.3 (2083.0)	2.50 (0.67, 5.00)
Reference	62894.1 (25405.3)	NC	5519.0 (2198.5)	2.00 (1.00, 6.00)
*Ratio (90% CI)	95.77 (91.06 – 100.73)		101.90 (94.62 – 109.74)
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

The intra-subject coefficient of variation was 20.6% and 13.6% for Cmax and AUCT, respectively.

Again, the terminal phase of UDCA could not be adequately estimated for almost all subjects. Tmax did not occur at the first sampling point in any of the subjects.

Table 2b. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD,

tmax median, range) for Baseline Corrected Total UDCA in USO-P1–498

Treatment	AUC 0-t ng/ml/h	AUC 0-∞ ng/ml/h	C max ng/ml	t max h
Test	57308.3 (20252.5)	NC	5535.9 (2070.3)	2.50 (0.67, 5.00)
Reference	60128.4 (23345.5)	NC	5481.1 (2179.6)	2.00 (1.00, 6.00)
*Ratio (90% CI)	95.89 (91.20 – 100.82)		101.98 (94.68 – 109.84)
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

The intra-subject coefficient of variation was 20.6% and 13.5% for Cmax and AUCT, respectively.

Again, the terminal phase of UDCA could not be adequately estimated for almost all subjects. Tmax did not occur at the first sampling point in any of the subjects.

The 90% CIs of the ratio of the test to reference product for the primary PK parameters Cmax and AUC0-t were contained within the prespecified acceptance range 80.00% to 125.00% to conclude bioequivalence. Endogenous levels of UDCA (baseline) were low or below LLOQ at most timepoints in most subjects. Thus, baseline-corrected and baseline-uncorrected results were very similar.

Baseline-corrected un-conjugated UDCA is considered most significant in the evaluation of bioequivalence of the two formulations and is supported by the similar baseline- uncorrected results for un-conjugated UDCA and the results for total UDCA. Fluctuations in the UDCA plasma concentrations were noted and may be explained by increases following meals and entero-hepatic recirculation of UDCA; however a contribution by late gastrointestinal absorption of UDCA (from colon) cannot be excluded. Due to the fluctuations observed, the terminal log-linear phase and AUCinf could not be characterized in almost all cases and as a consequence, AUC0–72h still needs to be reported via post-approval variation procedure as committed by the Applicant.

No new safety concerns arose in bioequivalence study USO-P1–498.

Biowaiver for additional strength

A biowaiver for additional strength is requested for the 500mg strength.

The composition of the two strengths of the test product are dose proportional. Since the two strengths of the test product; UDCA 250 mg capsules and UDCA 500 mg capsules are manufactured using a common blend, point a) to c) of the general biowaiver criteria can be regarded as fulfilled.

Comparative in vitro dissolution profiles at pH 8.4, pH7.5 and pH 6.8:

The obtained results using three different dissolution methods demonstrated similarity at all pH values in all comparisons using the Hotelling’s statistical approach whenever F2 calculation was not applicable.

For UDCA a less than proportional increase in AUC with increasing dose over the therapeutic dose range could not be ruled out based on the published literature. However, study USO-P1–498 may be considered sufficient for both strengths, since (i) UDCA is an endogenous substance and use of a dose of 2×250 mg instead of 1×250 mg in bioequivalence study USO-P1–498 enabled reliable determination of the concentrations above baseline (ii) the two strengths are made from one common blend, differing only in that the dose would be presented in one capsule instead of two. Considering that the point estimates in study USO-P1–498 were close to 100% with relatively low variability observed, this difference may be assumed negligible.

Although insufficient solubility of UDCA was demonstrated in acidic media and 0% dissolution was obtained for the reference Ursofalk 250mg at pH1.2 and 4.5, comparative dissolution data at pH1.2, 4.5 (without surfactants) incl. F2 statistics if applicable still need to be provided via post-approval variation procedure as committed by the Applicant (see section VI) in support of a biowaiver for additional strength, as laid down in the Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr, even if these conditions result in dissolution being negligible.

Summary Pharmacovigilance system

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.

Risk Management Plan

The MAH has submitted an updated risk management plan version 1.1 for Ursodesoxycholic acid 250mg/500 mg hard capsules in the format of GVP Module V rev 1. Data lock point was 31 December 2016; date of final sign-off was 17 January 2018. The RMP is for 2 medicinal products. It is a generic application. Therefore, part II SI-SVII has been omitted.

The applicant provided the following safety concerns:

Summary of safety concerns
Important identified risks	– Biliary colic – Decompensation of hepatic cirrhosis in patients with advanced stage of primary biliary cholangitis – Hypersensitivity and skin reactions – Calcification of gallstones (when used for the dissolution of gall stones or in non-authorised indications)
Important potential risks	– Teratogenicity
Missing information	– Safety in breastfeeding

The applicant considers routine pharmacovigilance measures and routine risk minimisation measures sufficient. This is agreed.

Summary of the RMP

The submitted Risk Management Plan, version 1.1 signed 11 December 2017 and established in the format of GVP Module V rev 1 is considered acceptable.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal 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 of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

Common renewal date

Common renewal date is 19.12.2023.

Legal status

Medicinal product subject to medical prescription.

User Test

Applying the criteria that each and every question must be answered correctly by at least 81% of the participants, the test did not produce a satisfactory outcome.

Hence the test does not sufficiently ensure that a user can find the information in the PIL, can understand it and can act properly after finding and understanding the information.

In addition, in the PIL tested, the recommended dosage is provided only in mg, but is not translated into the number of capsules that should be taken. This, however, is considered unacceptable in view of the fact that the pharmaceutical forms of both strengths of Nuzavi are indivisible capsules.

Of note, PIL submitted with the D160ARD along with the readability user test does not conform to the PIL tested in the user readability testing.

See also section V as regards second readability user testing with Nuzavi 250 mg and Nuzavi 500 mg package leaflets to be submitted via post-approval variation procedure prior to launch of Nuzavi 250mg and Nuzavi 500mg medicinal products.

IV. BENEFIT RISK ASSESSMENT

UDCA has a well-established efficacy and safety profile in the proposed indications.

Bioequivalence of the lower strength UDCA 250mg capsules and the reference Ursofalk 250mg hard capsules was demonstrated for both Cmax and AUCt for un-conjugated as well as total UDCA, both with and without baseline correction in the submitted bioequivalence study USO-P1–498 after administration of a single dose of 2 × 250mg.

For the 500mg strength, a biowaiver for additional strength has been applied for according to the provisions as laid down in the Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*. However, there are still some issues to be resolved via post-approval variation procedures as committed by the Applicant (see section VI): As regards bioequivalence study USO-p1–498, proof of suitability of a reference standard and two internal standards used for bioanalysis of study samples still needs to be documented and AUC0–72 needs to be reported for unconjugated as well as total UDCA, both with and without baseline correction.

As regards the biowaiver for additional strength, comparative dissolution data at pH1.2 and 4.5 (without surfactants) need to be provided as laid down in the Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*,even if these conditions result in dissolution being negligible.

Importantly, the pharmaceutical forms of both strengths of Nuzavi are indivisible capsules, unlike the originator’s 500mg strength, which is a film-coated tablet that can be divided into equal doses of 250 mg each to provide all recommended body weight dependent dosages in all three indications. Since there are at present no standards or regulatory requirements in the EU that specifically address scoring of tablets, this difference in scoring will have to be accepted, although consistent scoring would be considered preferable.

Commitment has been given by the Applicant to execute second readability user testing for the amended Nuzavi 250mg and Nuzavi 500mg package leaflets after closure of the procedure to be submitted via variation procedure to demonstrate that the package leaflets are legible, clear and easy to use. In addition the Applicant committed to change the colour of Nuzavi 250mg via post-approval variation procedure to reduce the risk of medication errors.

Importantly, the Applicant committed not to launch Nuzavi 250mg and Nuzavi 500mg prior to approval of all these data via post-approval variation procedures.

In view of the Commitments given by the Applicant to perform a number of post authorisation follow- up measures to be reported back to the RMS and CMS within predefined timeframe (see section V), and, importantly, not to launch Nuzavi 250mg and Nuzavi 500mg prior to approval of all these data via post-approval variation procedures, from a clinical point of view, Nuzavi 250mg / 500mg Hartkapseln may be recommended for marketing authorisation.

The application is approved. For intermediate amendments see current product information.

PROPOSED CONDITIONS FOR MARKETING

V. 1 Proposed list of conditions pursuant to Article 21a or 22 of Directive

2001/83/EC

Obligation to conduct post-authorisation measures in accordance with Article 21a of

Directive 2001/83

The MAH shall complete, within the stated timeframe, the below measures:

Description

Due date

1) POST-APPROVAL COMMITMENT

By post-approval commitment dated 5 December 2018, the Applicant gave the following commitment:

A second readability user testing with Nuzavi 250 mg and Nuzavi 500 mg package leaflets will be executed.

Prior to

marketing

Nuzavi 250 mg, 500 mg Hartkapseln

DE/H/5186/001–002/DC

Public Assessment Report

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