PUBLIC ASSESSMENT REPORT
Decentralised Procedure
Bosentan AL 62.5 mg & 125mg Procedure Number: DE/H/5017/001-002/DC
Bosentan STADA 62.5 mg & 125mg Procedure Number: DE/H/5018/001-002/DC
Active Substance Bosentan
Dosage Form Film Coated Tablets
Marketing Autorisation Holder STADA Arzneimittel
Publication: 12.10.2016
TABLE OF CONTENTS
I. EXECUTIVE SUMMARY ...... 3 II. SCIENTIFIC OVERVIEW AND DISCUSSION...... 4 II.1 Quality aspects ...... 4 II.2 Non-clinical aspects ...... 5 II.3 Clinical aspects...... 6 III. BENEFIT RISK ASSESSMENT...... 10 IV. PROPOSED LIST OF OUTSTANDING ISSUES ...... 10 IV.1 Quality aspects ...... 10 IV.2 Non-clinical aspects ...... 10 IV.3 Clinical aspects...... 10 V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION...... 10 V.1 Legal Status ...... 10 V.2 Proposed list of follow-up measures
DE/H/5017-5018/001-002/DC Public Assessment Report Page 2/12 RECOMMENDATION
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Bosentan AL/STADA 62.5 mg and Bosentan AL/STADA 125 mg film-coated tablets in the
Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in: • Primary (idiopathic and heritable) pulmonary arterial hypertension • Pulmonary arterial hypertension secondary to scleroderma without significant interstitial pu lmonary disease • Pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology
Some improvements have also been shown in patients with pulmonary arterial hypertension WHO functional class II (see section 5.1).
Bosentan is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1). is approvable.
I. EXECUTIVE SUMMARY
1. Problem statement
The medicinal products applied for were developed as generics to the bosentan containing originator product Tracleer.
2. About the product
Bosentan is a dual endothelin A and B (ETA and ETB) receptor antagonist that is indicated for the treatment of patients with primary or secondary pulmonary arterial hypertension. Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide whose actions are mediated through ETA receptors present on smooth muscle cells and endothelin B (ETB) receptors present on endothelial cells. Predominant actions of ET-1 binding to ETA receptors are vasoconstriction and vascular remodeling, while binding to ETB receptors results in ET-1 clearance and vasodilatory and antiproliferative effects due, in part, to nitric oxide and prostacyclin release. ET-1 concentrations are elevated in plasma and lung tissue of patients with PAH. ETA and ETB receptors play a key role in regulating vascular resistance in the lung by directly stimulating vasoconstriction and pulmonary vascular remodeling and this ultimately leads to progressive right heart failure.
3. General comments on the submitted dossier
This is an Application according to Article 10(1) of Directive 2001/ 83/ EC. With this decentralised application, Stada Arzneimittel AG is applying for a generic version of Bosentan under the trade names of Bosentan AL/STADA 62.5 mg and Bosentan AL/STADA 125 mg film-coated tablets. With Germany as the Reference Member State, Stada Arzneimittel AG is applying for Marketing Authorisations for Bosentan in DE, LU and FR.
The European Reference medicinal product is Tracleer 125 mg film-coated tablets manufactured by Actelion Registration Ltd, registered since 2002/05/17 in the EU (MA number EU/1/02/220/004-005).
Tracleer 125 mg is licensed for the following indications: Treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity and symptoms in patients with WHO functional class III. Efficacy has been shown in: • Primary (idiopathic and heritable) pulmonary arterial hypertension
DE/H/5017-5018/001-002/DC Public Assessment Report Page 3/12 • PAH secondary to scleroderma without significant interstitial pulmonary disease • PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger’s physiology Some improvements have also been shown in patients with PAH WHO functional class II (see section 5.1). Bosentan is also indicated to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease (see section 5.1).
The indications applied for are identical to those of the reference product.
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 all manufacturing sites valid GMP and QP declarations are presented in module 1. In the application form the manufacturing site Stadastrasse 2-18; 61118 Bad Vilbel, Germany is listed and the GMP certificates with STADA Arzneimittel AG state the above mentioned site address.
It is stated in the study report of the bioequivalence study submitted (study no.:1500) that the study was conducted in accordance with Good Clinical Practice, as established by the International Conference on Harmonization (ICH), the basic principles defined in Division 5 of the Canadian Food and Drug Regulations, the Belmont Report, the European Directive EC/2001, and the principles enunciated in the World Medical Association Declaration of Helsinki (Seoul, Korea, 2008). During assessment no issue of GCP non-compliance arose.
II. SCIENTIFIC OVERVIEW AND DISCUSSION
II.1 Quality aspects
Drug substance Bosentan monohydrate contained in the drug products applied for is manufactured by Amino Chemicals Ltd., Malta. A complete ASMF (Applicant’s and Restricted Parts) has been submitted in support of the application. A suitable declaration by the Qualified Person from the site responsible of batch release in DE regarding the GMP compliance by the drug substance manufacturer has been provided. The information relating to the drug substance provided in the Applicant’s Part is generally acceptable. A declaration by the QP of the manufacturing authorisation holder listed in the application form has been presented. This declaration confirms that the active substance is manufactured, at time point of the re-defined starting material, in accordance with the guidelines on GMP for starting materials as adopted by the community. Batch analysis data have been provided which show the drug substance to consistently meet the proposed specification. The drug substance appears to be stable, although the storage condition “Preserve in tight, light-resistant containers” is added. The restricted part of the ASMF is acceptable.
Drug Product The choice of excipients is acceptable and their functions explained. All excipients are well known and of appropriate quality. Further information is required regarding analytical method validation. The requested biowaiver for the Bosentan 62.5 mg film-coated tablet product is acceptable from the pharmaceutical point of view.
The manufacturing process has been suitably validated at the pilot scale (100,000 tablets) and has been shown to be capable of consistently producing drug products of acceptable quality. A validation protocol for the manufacture of the drug products at the commercial scale has been submitted. The drug product specification generally covers appropriate parameters for this dosage form type.
DE/H/5017-5018/001-002/DC Public Assessment Report Page 4/12 Validation information regarding the analytical methods (assay, dissolution and related substances) has been presented and is satisfactory. Batch analysis has been performed and the results show that the drug products meet the specifications proposed by the applicant. Sufficient stability data have been submitted and a shelf-life of 36 months without any storage conditions is acceptable for both products.
Commitments from the applicant:
The applicant regards the stability guideline and has stated “The shelf life commences from the mixing stage of API with the excipients”. Since the mixing of the API with the excipients is performed at the beginning of the manufacturing process it can be concluded that the shelf life is established in accordance with the respective stability guideline (CPMP/QWP/072/96, Note for guidance on start of shelf-life of the finished dosage form).
II.2 Non-clinical aspects
Pharmacology Bosentan is a competitive endothelin receptor antagonist (ERA) with affinity for both endothelin A and B (ETA and ETB) receptors. Bosentan has a slightly higher affinity for ETA receptors (Ki = 4.1—43 nM) than for ETB receptors (Ki = 38—730 nM) as determined in human smooth muscle cells (ETA) and human placenta and porcine trachea (ETB) (Clozel et al. 1994). Bosentan has a high selectivity for ETA and ETB receptors against other receptors (Clozel et al. 1994). Bosentan inhibits the ET-1-induced proliferarion of pulmonary artery smooth muscle cells (Yang et al. 1999). ET-1- induced contractions in rat aorta and sarafotoxin S6C (a selective ETB receptor agonist)-induced contractions in rat trachea were competitively inhibited by bosentan with pA values of 7.2 and 6.0, respectively, and the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery was inhibited by bosentan with a pA value of 6.7 (Clozel et al. 1994). In vivo, bosentan at doses of 3 – 30 mg/kg p.os and 10 mg/kg i.v. inhibits the pressor response effects of ET-1; bosentan has no intrinsic agonist activity (Clozel et al. 1994). Bosentan (100 mg/kg/die p.os for 2 days) inhibited the pulmonary vasoconstrictor response to acute hypoxia in the rat, and chronic bosentan administration (100 mg/kg/die p.os) prevented the development of pulmonary hypertension and attenuated right heart hypertrophy; administration of bosentan after hypoxia reversed hypoxia-induced pulmonary hypertension (Chen et al. 1995). Bosentan has been shown to improve survival rate and ameliorate end-organ damage in homozygous rats transgenic for the mouse Ren-2 renin gene without lowering blood pressure, and proteinuria, glomerulosclerosis and cardiac hypertrophy as well as ET-1 content in left ventricular tissue were reduced (Vaneckova et al. 2005).
Pharmacokinetics In humans, the absolute bioavailability of bosentan is approximately 50%. Bosentan is highly bound (> 98%) to plasma proteins, mainly albumin. The volume of distribution (Vss) is about 18 l, and the clearance is 8.2 l/h. The terminal elimination half- life (t1/2) is 5.4 hours. Bosentan is eliminated by biliary excretion following metabolism in the liver by the cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Bosentan forms three metabolites and only one of these is pharmacologically active. This metabolite is mainly excreted unchanged via the bile.
DE/H/5017-5018/001-002/DC Public Assessment Report Page 5/12 Upon multiple dosing, plasma concentrations of bosentan decrease to 50%—65% of those seen after single dose administration. This decrease is probably due to auto-induction of metabolising liver enzymes, because bosentan is an inducer of CYP2C9 and CYP3A4. In vitro data demonstrated that bosentan had no relevant inhibitory effect on the CYP isoenzymes tested (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4). Bosentan increases plasma concentrations of ET-1 (Weber et al. 1996, Dingemanse and van Giersbergeb 2004, SPC).
Toxicology Some ERAs (e.g. sitaxsentan, bosentan) induce hepatotoxicity in humans. It has been discussed that these effects are mediated by an inhibition of the bile salt export pump (BSEP) which exports bile salts out of hepatocytes into the bile, inducing bile salt accumulation in liver cells and cytolysis. In December 2010, sitaxsentan (Thelin®) was withdrawn due to its hepatotoxicity (EMA/CHMP/821121/2010). In rats, bosentan induces increases in plasma bile salt concentration. In dogs, cholestasis was observed after the administration of bosentan. In a 4 week study, bosentan induced increases in serum liver enzymes, bile duct proliferation and single cell necrosis at doses of 500 and 1000 mg/kg/die. In a 12 months study, bosentan induced pigment deposits in the liver and increased serum bile salts at a dose of 500 mg/kg/die. In humans, bosentan induces increases in bile salt concentrations followed by increases in liver enzymes.
A 2-year carcinogenicity study in mice showed an increased combined incidence of hepatocellular adenomas and carcinomas in males, but not in females, at plasma concentrations about 2 to 4 times the plasma concentrations achieved at the therapeutic dose in humans. In rats, oral administration of bosentan for 2 years produced a small, significant increase in the combined incidence of thyroid follicular cell adenomas and carcinomas in males, but not in females, at plasma concentrations about 9 to 14 times the plasma concentrations achieved at the therapeutic dose in humans. Bosentan was negative in tests for genotoxicity. There was evidence of a mild thyroid hormonal imbalance induced by bosentan in rats. However, there was no evidence of bosentan affecting thyroid function (thyroxine, TSH) in humans. Bosentan has been shown to be teratogenic in rats at plasma levels higher than 1.5 times the plasma concentrations achieved at the therapeutic dose in humans. Teratogenic effects, including malformations of the head and face and of the major vessels, were dose dependent. The similarities of the pattern of malformations observed with other ET receptor antagonists and in ET knock-out mice indicate a class effect. Appropriate precautions must be taken for women of child-bearing potential. In fertility studies in male and female rats at plasma concentrations 21 and 43 times, respectively, the expected therapeutic level in humans, no effects on sperm count, motility and viability, or on mating performance or fertility were observed, nor was there any adverse effect on the development of the pre-implantation embryo or on implantation (section 5.3 of the SPC). In conclusion, from a toxicological point of view, the major issues regarding bosentan are hepatotoxicity and teratogenicity.
II.3 Clinical aspects
To support this application, a report of the following bioequivalence study was submitted: A Single- Dose, Randomized, Open-Label, Replicate, Pivotal, Comparative Bioavailability Study of Bosentan 125 mg Film-Coated Tablets (PharOS Ltd., Greece) and Tracleer® 125 mg Film-Coated Tablets (Actelion Registration Ltd.) in Healthy Male Volunteers under Fasting Conditions.
The study was performed at the clinical facility of Bio Pharm Services Inc, Ontario, Canada. The study started on July 22, 2012 and was completed on August 14, 2012.
The formulation used in the bioequivalence study as the test product is the same as the to be marketed formulation.
The study consisted of four study periods. Each period included a single-dose drug administration of either test or reference product. There was a washout period of 7 days between each drug
DE/H/5017-5018/001-002/DC Public Assessment Report Page 6/12 administration. Subjects were randomly assigned to one of the two dosing sequences (A-B-A-B or B- A-B-A). Blood samples were taken at the following time points: pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 18, 24 and 36 hours after dosing.
The concentration of Bosentan was to be measured from plasma samples collected over a 36-hour interval after dosing in each study period. Pharmacokinetic parameters Cmax, Tmax, AUCt, AUCinf, AUC(res%), T1/2 and λ were estimated based on bosentan plasma levels for subjects included in the statistical analysis. The traditional BE range of 80-125% was employed for AUCt and Cmax.
The study conduct and statistical analyses are considered appropriate. The analytical method employed was found to be sufficiently accurate and sensitive to quantify bosentan in human plasma.
Mean results of the pharmacokinetic parameters are given in the following table:
The T/R ratios of geometric means, the corresponding 90% CIs and the intra-subject variability for the PK parameters were as follows:
It could be concluded that The Test/Reference ratio of geometric means and the corresponding 90% confidence interval for the AUCt and Cmax parameters were entirely contained within the acceptance range of 80.00%-125.00%. Therefore, in this study, bioequivalence was demonstrated between Bosentan 125 mg Film-Coated Tablets (PharOS Ltd., Greece) and Tracleer® 125 mg Film-Coated Tablets (Actelion Registration Ltd.) in normal, healthy male volunteers under fasting conditions. Standard safety monitoring was performed. Both test and reference products were well tolerated by the healthy subjects.
No in vivo study for the 62.5 mg dose strength was performed by the Applicant. The justification for the biowaiver is acceptable since - Bosentan showed linear pharmacokinetics up to doses of 500 mg (after multiple ascending oral doses
DE/H/5017-5018/001-002/DC Public Assessment Report Page 7/12 of 100, 200, 500, and 1000 mg Bosentan, plasma concentrations of Bosentan increased proportionally with doses up to and including a dose of 500 mg. Doses above 500 mg did not lead to significant further increases in plasma levels of Bosentan, e. g. Weber et al., J Clin Pharmacol, 1999). - both dosage strengths are manufactured by Biofarma Ilac Sanayi VE Ticaret AS, Istanbul, the manufacturing process is the same. - the qualitative and quantitative composition between the two strengths and the ratio between amounts of active ingredient and excipients is the same: - appropriate in vitro dissolution data confirm the adequacy of waiving additional in vivo bioequivalence testing (for details please refer to Clinical AR).
Pharmacovigilance system
Risk Management Plan At the start of this decentralised procedure the applicant submitted a new Risk Management Plan (version 1.0, sign off date 16-04-2014) which has been subsequently updated and amended to version 1.3 (sign off date 10-04.2015) according to the comments raised by the RMS at Day70 and Day120 of this procedure. The following safety concerns and risk minimisation measures are now proposed:
Important identified risks Safety concerns Routine risk minimisation measures Additional risk minimisation measure(s) Hypersensitivity Restricted medical prescription NA reactions Included in SPC section(s) - 4.8 Undesirable effects
Hepatotoxicity Restricted medical prescription Controlled distribution system Included in SPC section(s) similar to the originator - 4.4 Special warnings and Prescriber Kit precautions for use Patient alert card - 4.8 Undesirable effects
Teratogenecity Restricted medical prescription Controlled distribution system Included in SPC section(s) similar to the originator - 4.3 Contraindications Patient alert card - 4.4 Special warnings and Prescriber Kit precautions for use - 4.6 Fertility, pregnancy and lactation
Interaction with Restricted medical prescription Patient alert card hormonal Included in SPC section(s) contraceptives - 4.3 Contraindications - 4.4 Special warnings and precautions for use - 4.5 Interaction with other medicinal products and other forms of interaction - 4.6 Fertility, pregnancy and lactation
Interaction with Restricted medical prescription NA cyclosporine A Included in SPC section(s) - 4.3 Contraindications - 4.4 Special warnings and precautions for use - 4.5 Interaction with other medicinal products and other forms of
DE/H/5017-5018/001-002/DC Public Assessment Report Page 8/12 interaction
Decreased Restricted medical prescription Controlled distribution system haemoglobin levels Included in SPC section(s) similar to the originator - 4.4 Special warnings and Prescriber Kit precautions for use - 4.8 Undesirable effects
Pulmonary oedema Restricted medical prescription NA in patients with Included in SPC section(s) PVOD - 4.4 Special warnings and precautions for use
Concomitant use Restricted medical prescription Controlled distribution system with substrates, Included in SPC section(s) similar to the originator inducers or - 4.5 Interaction with other medicinal Prescriber Kit inhibitors of P450 products and other forms of isoenzymes interaction
Important potential risks Use in patients Restricted medical prescription NA with pulmonary Included in SPC section(s) arterial - 4.4 Special warnings and hypertension and precautions for use left ventricular failure Concomitant use Restricted medical prescription NA with antiretrovirals Included in SPC section(s) - 4.5 Interaction with other medicinal products and other forms of interaction
Missing information Use in patients Restricted medical prescription NA with severe Included in SPC section(s) pulmonary arterial - 4.2 Posology and method of hypertension administration - 4.4 Special warnings and precautions for use
Use in pregnancy Restricted medical prescription NA and during Included in SPC section(s) breastfeeding - 4.6 Fertility, pregnancy and lactation Use in children Restricted medical prescription NA Included in SPC section(s) - 4.2 Posology and method of administration
Periodic Safety Update Report (PSUR)
The next PSUR should 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.
DE/H/5017-5018/001-002/DC Public Assessment Report Page 9/12 III. BENEFIT RISK ASSESSMENT
The application contains an adequate review of published clinical data for bosentan in the indication applied for and bioequivalence of the product applied for with the reference product has been shown. Based on the data submitted the benefit/ risk is considered positive.
IV. PROPOSED LIST OF OUTSTANDING ISSUES
IV.1 Quality aspects none
IV.2 Non-clinical aspects none
IV.3 Clinical aspects none
V. PROPOSED CONDITIONS FOR MARKETING AUTHORISATION AND PRODUCT INFORMATION
V.1 Legal Status
Medical prescription
V.2 Proposed list of follow-up
Follow-up measures:
Area1 Description Pharmacovigilance Registry: a multicentre, prospective, observational, non-interventional programme to document adherence to SmPC requirements for liver function, pregnancy testing. Interim reports to be provided yearly with submission of PSUR. Quality The applicant has committed that a total of three production scale batches of each strength of Bosentan 62.5 and 125 mg film-coated tablets will be tested for stability. Quality The commitment is accepted and stability data to support the 36 months shelf- life will be available as soon the 36 month time point is reached and the analyses are completed. Quality The applicant commits to inform the authorities, if any result of the stability testing is out of the specification limits. Quality The applicant commits to validate the first three batches of each strength, whenever a new batch size of compression will be commercialized outside the validated range. Quality The applicant confirms that it is requested to develop post-approval, a new optimised in-vitro dissolution method (investigation of lower % of surfactant and other paddle speed). This new method will be used in development and submitted for any future variation which could impact the bioavailability of the active substance.
Specific Obligations:
DE/H/5017-5018/001-002/DC Public Assessment Report Page 10/12 none
V.3 Other conditions
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
Additional risk minimisation measures
Controlled Distribution system: The MAH shall agree the details of a controlled distribution system with the National Competent Authorities and must implement such programme nationally to ensure that prior to prescribing all health care professionals who intend to prescribe and/or dispense bosentan are provided with a Prescriber Kit containing the following: • Information about bosentan • Patient Information Booklet/Patient Alert Card
The information provided about bosentan shall contain the following key elements:
• That bosentan is teratogenic in animals o Use in pregnant women is contraindicated o The need for effective contraception o That there is an interaction with hormonal contraceptives o Monthly pregnancy tests in women of child bearing potential are recommended.
• That bosentan is hepatotoxic o bosentan should not be used in Child Pugh Class B or C, ie moderate to severe hepatic impairment. o Need for liver function tests to be measured: .Prior to initiation of treatment .At monthly intervals during complete course of the treatment .Two weeks after any dose increase.
o Need for close monitoring and dosage adjustment if levels rise above 3 x upper limit normal (ULN):
.>3 and ≤ 5 x ULN: Confirm levels and if confirmed, reduce the daily dose or stop treatment and monitor liver function at least every 2 weeks. .>5 and ≤ 8 x ULN: Confirm levels and if confirmed stop treatment and monitor liver function at least every 2 weeks. In the above circumstances, if the levels return to pre-treatment values, continuing or re- introducing bosentan may be considered. .> 8 x ULN or any of the above with associated clinical symptoms of liver injury: Treatment must be stopped and re-introduction of bosentan is not to be considered.
• That treatment with bosentan is associated with a decrease in haemoglobin. o Need for blood monitoring .Prior to initiation of treatment .Monthly during the first 4 months .Quarterly thereafter.
• That co-administration of bosentan with cyclosporine is contraindicated. • That the safety database of bosentan in the indication to reduce the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease is limited and physicians are encouraged to enrol patients in the surveillance programme/registry to further increase knowledge about the product. The surveillance programme/registry should prompt doctors to report adverse reactions.
DE/H/5017-5018/001-002/DC Public Assessment Report Page 11/12
The patient information shall contain the following information: • That bosentan is teratogenic in animals • That pregnant women must not take bosentan • That women of child bearing potential must use effective contraception • That hormonal contraceptives on their own are not effective • The need for regular pregnancy tests • That bosentan causes a decrease in haemoglobin and the need for regular blood tests • That bosentan is hepatotoxic and the need for regular monitoring of liver function.
The Patient Alert Card:
• Patient Alert Card specifically aimed at facilitating patients’ awareness of the need for regular blood tests for liver function. • Patient Alert Card specifically aimed at informing patients of the need to avoid pregnancy and to ensure effective contraceptive measures are used.
Surveillance programme/Registry The MAH shall set up or participate in a multicentre, prospective, observational, non-interventional surveillance programme/registry to document adherence to SmPC requirements for liver function, pregnancy testing and the use of adequate contraception in these patients; Details of the operation of/participating in the surveillance programme/registry shall be agreed with the National Competent Authorities in each Member State.
V.4 Summary of Product Characteristics (SPC)
The Patient Information (SPC and PIL) submitted is fully in line with the patient information of the Originator Tracleer.
V.5 Package Leaflet (PL)
V.5.1 Package Leaflet
The Patient Information (SPC and PIL) submitted is fully in line with the patient information of the Originator Tracleer.
V.5.2 Assessment of User Testing
A user testing (Report dated 31. July 2013, test conducted by Creative Pharma Solutions, Czech Republic) has been performed in accordance with the requirements as stated in Articles 59(1) and 59(3) of Council Directive 2001/83/EC, Article 63(2) of Directive 2001/83/EC as amended, the European Commission document “Guideline on the readability of the labelling and package leaflet of medicinal products for human use” and MHRA guidance: the package leaflet has been successfully user tested. It has been identified that the information as presented, conveys the correct messages to those who read it. In the First Round, 100% of participants were able to find the correct information, and 100% of participants were able to answer the questions correctly. In the Second Round, 100% of participants were able to find the correct information.
V.6 Labelling n.a.
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