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PUBLIC ASSESSMENT REPORT


of the Medicines Evaluation Board
in the Netherlands

UDCA Tramedico 250 and 500,


film-coated tablets 250 mg and 500 mg
Tramedico B.V., the Netherlands

ursodeoxycholic acid
This assessment report is published by the MEB pursuant Article 21 (3) and (4) of Directive 2001/83/EC. The report
comments on the registration dossier that was submitted to the MEB.
It reflects the scientific conclusion reached by the MEB at the end of the evaluation process and provides a summary
of the grounds for approval of a marketing authorisation.
This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare
professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the
latter category as the language in this report may be difficult for laymen to understand.

This assessment report shall be updated by a following addendum whenever new information becomes available.

General information on the Public Assessment Reports can be found on the website of the MEB.

To the best of the MEBs knowledge, this report does not contain any information that should not have been made
available to the public. The MAH has checked this report for the absence of any confidential information.

Registration number in the Netherlands: RVG 111016-111017

20 March 2014

Pharmacotherapeutic group: bile acid preparations


ATC code: A05AA02
Route of administration: oral
Therapeutic indication: dissolution of cholesterol gallstones; primary biliary cirrhosis
(PBC); adjuvant medication in lithotripsy; treatment of chronic
mild to moderate hepatobiliary disorders due to cystic fibrosis in
children and adolescents
Prescription status: prescription only
Date of authorisation in NL: 18 March 2013
Application type/legal basis: Directive 2001/83/EC, Article 10a

For product information for healthcare professionals and users, including information on pack sizes and
presentations, see Summary of Product Characteristics (SmPC), package leaflet and labelling.

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I INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Medicines Evaluation Board of the
Netherlands (MEB) has granted a marketing authorisation for UDCA Tramedico 250 and 500, film-coated
tablets 250 mg and 500 mg from Tramedico B.V. The date of authorisation was on 18 March 2013 in the
Netherlands.

The product is indicated for:


dissolution of cholesterol gallstones in patients
o with one or more radiolucent (i.e. non-radio opaque) cholesterol gallstones, preferably
less than 2 cm in diameter, in a well functioning gallbladder
o who refuse surgical intervention or in whom surgical intervention is not indicated
o in whom super saturation of cholesterol has been demonstrated in chemical analysis of
bile samples obtained by duodenal drainage
adjuvant medication before and after lithotripsy
primary biliary cirrhosis (PBC)
treatment of chronic ( 6 months) mild to moderate hepatobiliary disorders due to cystic fibrosis in
children and adolescents.

A comprehensive description of the indications and posology is given in the SmPC. Three additional
indications were applied for: primary sclerosing cholangitis, intrahepatic cholestasis during pregnancy in
the second and third trimester and ABCB4 deficiency-associated cholestasis and cholesterol lithiasis.
These are discussed in section II.3 Clinical aspects.

Ursodeoxycholic acid (UDCA) is a bile acid which effects a reduction in cholesterol in biliary fluid primarily
by dispersing the cholesterol and forming a liquid-crystal phase. UDCA affects the enterohepatic
circulation of bile salts by reducing the reabsorption in the intestine of endogenous more hydrophobic and
potentially toxic salts such as cholic and chenodeoxycholic acids.

In-vitro studies show that UDCA has a direct hepatoprotective effect and reduces the hepatotoxicity of
hydrophobic bile salts.

This national procedure concerns a bibliographical application based on well-established medicinal use of
UDCA tablets. This type of application does not require submission of the results of pre-clinical tests or
clinical trials if the applicant can demonstrate that the active substance of the medicinal product has been
in well-established medicinal use within the Community for at least 10 years, with recognised efficacy and
an acceptable level of safety. Medicinal use does not exclusively mean use as an authorised medicinal
product, so that the proof of medicinal use may be submitted even in the absence of a marketing
authorisation. Well-established use refers to the use for a specific therapeutic use. For this kind of
application, a detailed description of the strategy used for the search of published literature and the
justification for inclusion of the references in the application has to be provided. The documentation
submitted by the applicant should cover all aspects of the assessment and must include a review of the
relevant literature, taking into account pre- and post-marketing studies and published scientific literature
concerning experience in the form of epidemiological studies and in particular of comparative
epidemiological studies.

The marketing authorisation is granted based on article 10a of Directive 2001/83/EC.

No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application.

No scientific advice has been given to the MAH with respect to these products and no paediatric
development programme has been submitted, which is acceptable for this kind of application.

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II SCIENTIFIC OVERVIEW AND DISCUSSION

II.1 Quality aspects

Compliance with Good Manufacturing Practice


The MEB has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for
this product type at all sites responsible for the manufacturing of the active substance as well as for the
manufacturing and assembly of this product prior to granting its national authorisation.

Active substance
The active substance is ursodeoxycholic acid (UDCA), an established active substance described in the
European pharmacopoeia (Ph.Eur.*). The active substance is a white or almost white powder, which is
practically insoluble in water, freely soluble in ethanol, slightly soluble in acetone, and practically insoluble
in methylene chloride and in water. No polymorphism is known for UDCA.

The CEP procedure is used for the active substance. Under the official Certification Procedures of the
EDQM of the Council of Europe, manufacturers or suppliers of substances for pharmaceutical use can
apply for a certificate of suitability concerning the control of the chemical purity and microbiological quality
of their substance according to the corresponding specific monograph, or the evaluation of reduction of
Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This
procedure is meant to ensure that the quality of substances is guaranteed and that these substances
comply with the European Pharmacopoeia.

Manufacturing process
A CEP has been submitted; therefore no details on the manufacturing process have been included.

Quality control of drug substance


The drug substance specification is in line with the Ph.Eur. and the CEP, with additional requirements for
particle size distribution. Batch analytical data demonstrating compliance with the drug substance
specification have been provided for three full-scale batches.

Stability of drug substance


The active substance is stable for 60 months when stored under the stated conditions. Assessment
thereof was part of granting the CEP and has been granted by the EDQM.

*Ph.Eur. is an official handbook (pharmacopoeia) in which methods of analysis with specifications for
substances are laid down by the authorities of the EU.

Medicinal Product

Composition
UDCA Tramedico 250 are white, round, biconvex film-coated tablets scored and engraved I025 on one
side. The tablet cannot be divided into equal halves. The score line on the 250 mg tablets is for ease of
swallowing.
UDCA Tramedico 500 a tablets are white or off-white, oval, biconvex film-coated tablets with a score line
on one side and engraved IO 50 on the other side. The tablet can be divided into equal halves.

The film-coated tablets are packed in PVC/Al blisters.

The excipients are:


Tablet core - maize starch, sodium lauryl sulfate, povidone, colloidal silica and magnesium stearate.
Film coating - titanium dioxide, anhydrous glucose, hypromellose and propylene glycol.

The two strengths are fully dose proportional with respect to their tablet cores. The amount of film-coat is
3.0% of the tablet core weight for the 250 mg and 2.0% for the 500 mg tablet.
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Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. The choices of the packaging and manufacturing process are justified.
A comparative dissolution study has been therefore conducted between UDCA Tramedico 250 and 500
mg film-coated tablets, showing comparable dissolution profiles.
Equal divisibility of the 500 mg tablets was adequately demonstrated in accordance with the Ph.Eur.
general monograph on tablets. The development of the product has been adequately performed.

Manufacturing process
The manufacturing process mainly consists of dry mixing, wet granulation, drying and screening,
lubrication, compression and coating. The manufacturing process has been adequately validated
according to relevant European guidelines. Process validation data on the product has been presented for
three full-scale batches per strength.

Control of excipients
The excipients comply with Ph.Eur. requirements. These specifications are acceptable.

Quality control of drug product


The product specification includes tests for appearance, identity, average mass, uniformity of dosage
units, breakability (only 500 mg), dissolution, assay, related substances and microbiological
contamination. The release and shelf-life requirements are identical. The specification is acceptable. The
analytical methods have been adequately described and validated. Batch analytical data from the
proposed production site have been provided on three full-scale batches per strength, demonstrating
compliance with the release specification.

Stability of drug product


Stability data on the product has been provided on six full-scale batches of 250 mg and three full-scale
batches of 500 mg stored at 25C/60% RH (18-36 months) and 40C/75% RH (6 months, performed for
three batches per strength). The conditions used in the stability studies are according to the ICH stability
guideline. The batches were stored in PVC/Al blisters. No changes or trends are seen at both storage
conditions. No degradation was observed from light. On the basis of the results of the forced degradation
studies the proposed shelf-life of 36 months without any special storage requirements is justified.

Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
The active substance ursodeoxycholic acid is produced from animal derived material, bovine bile, for
which a TSE certificate of suitability has been granted. No excipients of human or animal origin are used
in the manufacture of the drug product. Magnesium stearate and sodium lauryl sulfate are of vegetable
origin..

II.2 Non-clinical aspects

According to Article 10a of Directive 2001/83/EC, it is possible to replace results of pre-clinical trials by
detailed references to published scientific literature (information available in the public domain), if it can be
demonstrated that the active substance has been in well-established medicinal use within the Community
for at least 10 years for the same indication, with recognized efficacy and an acceptable level of safety.

The active compound of UDCA Tramedico tablets is ursodeoxycholic acid. This compound is a gallstone
dissolving agent, which acts by reducing the content of cholesterol in bile, due either to a reduction in
hepatic cholesterol synthesis or reduced absorption of cholesterol or both. The provided Nonclinical
Overview is adequate.

In the Netherlands, ursodeoxycholic acid is a well-known active substance in medicinal products for
treatment of biliary cirrhosis and for the dissolution of small and medium sized cholesterol-rich gall-stones.
These products include, among others, Ursochol 150, 300, 450, tablets (NL License RVG 07718, 09307,

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29828) and Ursofalk capsules 250 mg (RVG 08384). Both are registered products in the Netherlands for
more than ten years.

The provided literature data justify why there is no need to generate additional non-clinical pharmacology,
pharmacokinetics and toxicology data. Therefore, the Board agreed that no further non-clinical studies are
required.

Environmental risk assessment


The approval of this product will not result in an increase in the total quantity of ursodeoxycholic acid
released into the environment. It does not contain any component, which results in an additional hazard to
the environment during storage, distribution, use and disposal.

II.3 Clinical aspects

Ursodeoxycholic acid is a well-known active substance with established efficacy and tolerability. The
dossier is based on well-established use of UDCA. The MAH summited a clinical overview for the
justification of the proposed indications and posology. Sufficient literature references were provided.

Pharmacokinetics
For this bibliographic application the MAH justified that the tablets to be marketed are representative for
the formulations indicated in the submitted literature, i.e. it should be substantiated that differences in
formulations and excipients do not affect bioavailability and absorption.

The composition of UDCA Tramedico 250 and 500 mg tablets is comparable to the composition of the
registered Ursofalk capsules. In the Ursochol tablets no lauryl sulphate is used, an excipient which may
affect absorption.
As UDCA has a low solubility at a pH of 1-7, dissolution data are normally obtained at a higher pH. For
dissolution testing, a QC medium at pH 8.0 has been used. Comparable dissolution was shown between
the 250 and 500 mg tablets versus the registered Ursofalk 250 mg capsule.

As UDCA acts in the bile and is extracted by the liver after absorption, before reaching the systemic
circulation, it can be questioned to which extent systemic concentrations are predictive for the effect.
Moreover, demonstration of bioequivalence is not required for this well-established use procedure.
Comparable bioavailability is justified with regard to Ursofalk capsules based upon dissolution data and
included excipients.

Clinical experience
Since 1976, the following indications are approved in the Netherlands for the innovator product Ursochol:

dissolution of cholesterol gallstones in patients


o with one or more radiolucent (i.e. non-radio opaque) cholesterol gallstones, preferably
less than 2 cm in diameter, in a well functioning gallbladder
o who refuse surgical intervention or in whom surgical intervention is not indicated
o in whom super saturation of cholesterol has been demonstrated in chemical analysis of
bile samples obtained by duodenal drainage
adjuvant medication before and after lithotripsy
primary biliary cirrhosis (PBC)
treatment of chronic ( 6 months) mild to moderate hepatobiliary disorders due to cystic fibrosis in
children and adolescents.

The MAH applied for these indications. Additionally, three other indications were applied for: primary
sclerosing cholangitis, intrahepatic cholestasis during pregnancy in the second and third trimester and
ABCB4 deficiency-associated cholestasis and cholesterol lithiasis. These are assessed below.

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ABCB4 deficiency-associated cholestasis and cholesterol lithiasis


Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4
mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis.

Progressive familial intrahepatic cholestasis (PFIC) summarizes a group of three inherited cholestatic
diseases which may start early after birth or at young age and may rapidly progress to end-stage disease
(Oude Elferink et al., 2006). Mutations in canalicular transporter genes of the ATP-binding cassette (ABC)
transporters are responsible for these rare disorders. Three different stages can be defined: PFIC type 1,
2 and 3. These are rare chronic progressive cholestatic disorders of early childhood and adolescence.
PFIC type 1 and 2 are characterized by low GT, severe pruritus and various extrahepatic manifestations
(EASL, 2009).

PFIC type 3 typically presents in the first years of childhood with progressive cholestasis (Trauner et al.,
2007), although disease manifestation and cirrhosis in adulthood has also been described most recently
(Gotthardt, 20081). In contrast to PFIC1 and PFIC2, GT is usually markedly elevated in PFIC3 and
histology reveals, in addition to portal inflammation and fibrosis/cirrhosis, massive bile duct proliferation.
PFIC3 may be associated with intrahepatic gallstone disease. PFIC3 is caused by mutations in the
ABCB4 gene which encodes the canalicular phospholipid transporter, ABCB4/MDR3 (Trauner, 20072).

The MAH claims that UDCA is recommended in the patients having cholestasis associated with
monoallelic or missense ABCB4 mutations according to the EASL guideline (2009). However, according
to the EASL guideline there is no medical therapy of proven benefit for long term prognosis of PFIC.
UDCA has been reported to improve biochemical tests in almost 50% of patients with PFIC3 (Jacquemin,
20013), but generally does not affect PFIC1 and PFIC2.

The MEB is of the opinion that the submitted data is too limited and not robust enough to justify the MAHs
proposed indication in this specific subset of patients. More well designed studies are required to definitely
assess the efficacy of UDCA in the treatment of these specific indications in these subsets. The proposed
indications do not meet the requirements of well-established use, i.e. medicinal use in the Community for
at least 10 years. However, the Board considers that dissolving cholesterol stones as a result of these
genetic mutations in the ABCB4 gene are covered by the currently approved indication dissolution of
cholesterol gallstones in patients in whom super saturation of cholesterol has been demonstrated in
chemical analysis of bile samples obtained by duodenal drainage.

Primary sclerosing cholangitis


Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an
inflammatory and fibrotic process affecting both intra and extrahepatic bile ducts. The disease leads to
irregular bile duct obliteration, including formation of multifocal bile duct strictures. PSC is a progressive
disorder that eventually develops into liver cirrhosis and liver failure. The aetiology of PSC is unknown, but
there is evidence that genetic susceptibility factors are involved. The male to female ratio is approximately
2:1. PSC can be diagnosed in children as well as in the elderly, but mean age at diagnosis is around 40
years. Up to 80% of PSC patients have concomitant inflammatory bowel disease (IBD) that in the majority
of cases is diagnosed as ulcerative colitis (UC). Thus, the typical PSC patient is a young to middle-aged
man with IBD who presents with biochemical and/or clinical signs of a cholestatic liver disease (EASL,
20094).

1
Gotthardt D, Runz H, Keitel V, Fischer C, Flechtenmacher C, Wirtenberger M, et al. A mutation in the canalicular
phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology
2008;48:11571166
2
Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic
syndromes. Semin Liver Dis. 2007 Feb;27(1):77-98
3
Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three
diseases. Semin Liver Dis 2001;21:551562.
4
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver
diseases. J Hepatol 2009;51(2):237-67.
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A variety of immunosuppressive and anti-inflammatory agents have been studied in patients with PSC.
These include:
Ursodeoxycholic acid
Glucocorticoids
Cyclosporine
Methotrexate
Azathioprine and 6-mercaptopurine
Tacrolimus
D-penicillamine
Etanercept

Unfortunately, none of these has been conclusively proven to alter the natural history of this disorder.
Liver transplantation is currently the only option in end-stage PSC (Boonstra, 20105). However the disease
can reoccur after transplantation.

With respect to the indication primary sclerosing cholangitis, the Board noted that UDCA showed
improvement in liver biochemistries, however the clinical relevance can be seriously questioned. There
are no convincing beneficial effects of UDCA on death, liver complications which are considered clinically
relevant in PSC patients. Moreover, a recently published study showed that long-term use of high-dose
UDCA (28-30 mg/kg/day) in the treatment of PSC is associated with an increased risk of colorectal
neoplasia in patients with both ulcerative colitis (UC) and PSC (Eaton et al. 20116). Based on the
submitted data, the proposed indication is not approvable.

Intrahepatic cholestasis of pregnancy


Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, is a reversible form of
cholestasis characterized by:
(i) intense pruritus in pregnancy (starting in the second or third trimester of pregnancy in most patients),
(ii) elevated serum ALT activities and fasting serum bile acid levels,
(iii) spontaneous relief of signs and symptoms after delivery (within 46 weeks) (Lammert, 20007; Pusl,
20078).

In Europe, about 0.42.0% of pregnancies are affected (Pusl, 2007; Glantz, 20049). The clinical
importance of ICP lies in the potential fetal risks (spontaneous or iatrogenic prematurity, asphyxia events
during delivery, intrauterine death), albeit perinatal mortality rates from recent studies (9/1000) are
comparable to whole population figures, most likely due to improvements in obstetric and neonatal care
(RCOG, 200610). Pruritus (typically worse at night) impairs the mothers quality of life.

Only infrequently, ICP is associated with steatorrhea and postpartum haemorrhage due to vitamin K
deficiency. The pathogenesis of ICP is multifactorial, with genetic, hormonal and environmental factors
playing important roles. During ICP, there is an increased flux of bile acids from the mother to the fetus, as
indicated by elevated bile acid levels in amniotic fluid, cord blood and meconium (Brites, 200211).
Although essentially benign from a maternal viewpoint, ICP is associated with increased fetal risks, such
as preterm delivery in 19% to 60% fetal distress in 22%-41%, and intrauterine fetal death in 1% to 4% of

5
Boonstra K, Cyriel IJ. Ponsioen, Erik A.J. Rauws, Ulrich Beuers. Primaire scleroserende cholangitis. Ned Tijdschr
Geneeskd. 2010;154:A1476.
6
Eaton et al.: High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients
with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011 Sep;106(9):1638-45.
7
Lammert F, Marschall HU, Glantz A, Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis,
diagnosis and management. J Hepatol 2000;33:10121021.
8
Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis 2007;2:26.
9
Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy. Relationships between bile acid levels
and fetal complication rates. HEPATOLOGY 2004;40:467-474.
10
Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. RCOG Guideline No. 43, 2006:110.
11
Brites D. Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by
ursodeoxycholic acid. Ann Hepatol 2002;1:2028.
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affected pregnancies. Fetal complication rates are related to maternal serum bile acid levels, and increase
when bile acid levels exceed 40 mol/L (Glantz 200512).

Treatment for ICP focuses on reducing symptoms and preventing maternal and fetal complications.
Several drugs have been studied, and most focus on relieving symptoms. UDCA (10-20 mg/kg/day) is
considered as the first line treatment for ICP (EASL, 2009).

Initial pilot studies in ICP followed by controlled trials demonstrated that UDCA improved pruritus and liver
tests, and had no adverse effects in the mothers or babies.

A concern with UDCA therapy is that bile acids can cross the placenta, which might lead to fetal toxicity.
However, one study found that treatment restored the serum bile acid composition to more closely
resemble that seen in healthy, pregnant controls, while in another report, meconium bile acid
concentrations were not affected by maternal UDCA administration. Accumulation in the amniotic fluid and
cord blood appears to be very low even when high doses of UDCA (1.5 to 2.0 g/day) have been given.

Several other treatments such as hydroxyzine (25 to 50 mg/day) and cholestyramine (8 to 16 g/day) for
ICP may be beneficial in individual patients. Both drugs have their drawbacks. Antihistamines can
aggravate respiratory difficulties in preterm babies and cholestyramine was less effective than UDCA.

The Board questions whether use of UDCA in the treatment of Intrahepatic cholestasis during pregnancy
in the second and third trimester can be considered well-established. Although the MAH submitted a fair
amount of literature from 1992 up to 2009, only a few publications are older than a decade. The use of
UDCA in the treatment was mentioned only in a Dutch guideline zwangerschapscholestase of March
2011 (NOVG). Well-established use means use in clinical practice for a particular indication for more 10
years. As this justification for the well-established use of UDCA could not be provided, the Board
considers inclusion of the indication intrahepatic cholestasis of pregnancy not approvable.

Safety
The MAH submitted an overview of safety information especially in the studies with pregnant women.
UDCA seem well tolerated by the patients. UDCA seems well tolerated in patients. Based on the long
term usage of UDCA in the already approved indications, side effects that occur are: diarrhea, severe
abdominal pain in the treatment of primary biliary sclerosis, liver cirrhosis in the treatment of primary biliary
sclerosis, and urticaria.

Regarding UDCA in pregnant women it can be concluded that UDCA is safe and that reported preterm
delivery seems not related to UDCA, as it was also reported that UDCA might have a beneficial effect in
delaying preterm delivery compared to placebo and compactor.

Risk management plan


The MAH has a pharmacovigilance system at their disposal, which is based on the current European
legislation. Routine pharmacovigilance activities are sufficient to identify actual or potential risks. The
safety profile of UDCA Tramedico tablets is expected to be similar to that of Ursochol capsules. No
additional risk management activities are considered necessary.

Product information

SmPC
The content of the SmPC approved during the national procedure is in accordance with those accepted
for other, comparable UDCA products.

Readability test

12
Glantz A, Marschall HU, Lammert F, Mattsson LA. Intrahepatic cholestasis of pregnancy: a randomized controlled
trial comparing dexamethasone and ursodeoxycholic acid. HEPATOLOGY 2005;42:1399-1405
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The package leaflet has been evaluated via a user consultation study in accordance with the requirements
of Articles 59(3) and 61(1) of Directive 2001/83/EC. The test consisted of a pilot test with 5 participants,
followed by two rounds with 10 participants each. The questions covered the following areas sufficiently:
traceability, comprehensibility and applicability. In both test rounds 100% of the questions were answered
correctly. The readability test has been sufficiently performed.

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III OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT


UDCA Tramedico 250 and 500, film-coated tablets have a proven chemical-pharmaceutical quality and
are well-established medicinal products. Based on the submitted dossier and further literature, UDCA
Tramedico can be considered effective in the dissolution of cholesterol gallstones, primary biliary cirrhosis
(PBC), as adjuvant medication in lithotripsy and for treatment of chronic mild to moderate hepatobiliary
disorders due to cystic fibrosis in children and adolescents.

Three additional indications were applied for: primary sclerosing cholangitis, intrahepatic cholestasis
during pregnancy in the second and third trimester and ABCB4 deficiency-associated cholestasis and
cholesterol lithiasis. In the Board meeting of 11 April 2012, these were discussed. The Board considered
that for ABCB4 deficiency-associated cholestasis and cholesterol lithiasis, as well as primary sclerosing
cholangitis the well-established medicinal use was insufficiently demonstrated. The MAH chose not to
pursue any of the additional indications.

The MAH has provided written confirmation that systems and services are in place to ensure compliance
with their pharmacovigilance obligations.

The SPC, package leaflet and labelling include adequate information and are in the agreed templates.

The MEB, on the basis of the data submitted, considered well-established medicinal use sufficiently
demonstrated for the above mentioned indications and has therefore granted a marketing authorisation.
UDCA Tramedico 250 and 500, film-coated tablets was authorised in the Netherlands on 18 March 2013.

There were no post-approval commitments made during the procedure.

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List of abbreviations
ASMF Active Substance Master File
ATC Anatomical Therapeutic Chemical classification
AUC Area Under the Curve
BP British Pharmacopoeia
CEP Certificate of Suitability to the monographs of the European Pharmacopoeia
CHMP Committee for Medicinal Products for Human Use
CI Confidence Interval
Cmax Maximum plasma concentration
CMD(h) Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
CV Coefficient of Variation
EASL European Association for the Study of the Liver
EDMF European Drug Master File
EDQM European Directorate for the Quality of Medicines
EU European Union
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
IBD Inflammatory Bowel Disease
ICH International Conference of Harmonisation
LPAC Low Phospholipid-associated Cholelithiasis
MAH Marketing Authorisation Holder
MEB Medicines Evaluation Board in the Netherlands
NOVG Nederlandse Vereniging voor Obstetrie en Gynaecologie (Dutch Society of
Obstetrics and Gynaecology)
OTC Over The Counter (to be supplied without prescription)
PAR Public Assessment Report
PFIC Progressive Familial Intrahepatic Cholestasis
Ph.Eur. European Pharmacopoeia
PIL Package Leaflet
PSC Primary Sclerosing Cholangitis
PSUR Periodic Safety Update Report
RCOG Royal College of Obstetricians and Gynaecologists
SD Standard Deviation
SmPC Summary of Product Characteristics
t Half-life
tmax Time for maximum concentration
TSE Transmissible Spongiform Encephalopathy
UC Ulcerative Colitis
USP Pharmacopoeia in the United States

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY


Scope Procedure Type of Date of start Date of Approval/ Assessment
number modification of the end of the non report
procedure procedure approval attached

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