Acetylcystein Stirling Anglian 600 mg Brausetabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Name of the medicinal product in the RMS	Acetylcystein Stirling Anglian 600 mg Brausetabletten
Name of the drug substance (INN name):	Acetylcystein
Pharmaco-therapeutic group (ATC Code):	R05CB01
Pharmaceutical form(s) and strength(s):	Effervescent tablet, 600 mg
Reference Number(s) for the Decentralised Procedure	DE/H/5408/001/DC
Reference Member State:	DE
Concerned Member States:	IE, MT, UK
Legal basis of application:	Bibliographic Art 10 a Dir 2001/83/EC
Applicant (name and address)	Stirling Anglian Pharmaceuticals Limited Hillington Park Innovation Centre Ainslie Road, Hillington Park GB-G52 4RU GLASGOW, United Kingdom
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Hermes Arzneimittel GmbH Georg-Kalb-Straße 5–8 D-82049 Großhesselohe Germany Hermes Arzneimittel GmbH (BS 1) Hans-Urmiller-Ring 52 D-82515 Wolfrat­shausen Germany

• I. INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Acetylcystein

Stirling Anglian 600 mg Brausetabletten in the following indication:

“in adults as a mucolytic agent for the treatment of respiratory tract diseases in which a reduction in bronchial secretion viscosity is required to facilitate expectoration (POM status). “

is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

This is a bibliographic application for Acetylcysteine 600 mg effervescent tablets, submitted under Article 10(a), Directive 2001/83/EC. With DE as RMS in this decentralised procedure the applicant is also seeking marketing authorisation in IE, MT and UK.

The active substance is acetylcysteine and the pharmaceutical form is an effervescent tablet with the strength of 600 mg.

A 600 mg effervescent tablet preparation of acetylcysteine was first licensed in the European Union on 8 August 1995 (Fluimucil Hustenlöser akut 600 mg Effervescent Tablets, licensed to Zambon GmbH, Germany).

• II.2 About the product

Acetylcysteine belongs to the ATC Code R05CB01 and acts as an expectorant.

All clinical raised points are resolved and from the clinical point of view the application is approvable.

The dosage regimen is:

“Adults:

600 mg acetylcysteine once daily.

Paediatric population:

Children aged 2 years and older, and adolescents under 18 years of age

The safety and efficacy of <Invented name> in children aged 2 years and older, and adolescents, have not been established.

Children under 2 years of age

<Invented name> is contraindicated in children 0 to 2 years.

Duration of therapy

Duration of therapy should be determined by the clinician, depending on the nature and severity of the condition “

• II.3 General comments on the submitted dossier

The submitted dossier is in line with current requirements. The drug substance is not considered as new active substance. Acetylcysteine is part of the Ph. Eur. monograph section.

The MAA for this product is applied for according to Art 10a of 2001/83 as amended. It is agreed that the active substance acetylcysteine has a ‘well-established use’ within the European Community for at least 10 years. Thus, the legal basis for the application is acceptable.

• 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. A QP declaration has been submitted.

GMP active substance

Regarding the statement on GMP for the active substances a statement/decla­ration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. For both manufacturers GMP certificates are submitted.

No own clinical studies have been provided as it is a bibliographic application. It is not possible to verify the GCP compliance for the quoted publications, but there are no identifiable risks.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

Drug substance

The drug substance, acetylcysteine, used for the manufacturing of the drug products, is monographed in the Ph.Eur. It is supplied by two manufacturers.

The quality of the drug substance is controlled in compliance with the corresponding monograph of the Ph. Eur. The suitability of the monograph to the drug substances has been verified by EDQM. Certificates of suitability have been granted, a copy of the current version of the respective certificate is provided for acetylcysteine supplied by both manufacturers. A declaration that no materials derived from human or animal origin are used during the drug substance manufacturing process is stated on both CEPs. A compiled specification for each of the suppliers has been presented from the drug product manufacturer.

The CEPs from both manufacturers state a re-test period of 5 years without storage conditions, if stored in double polyethylene bags placed in fibre board drums (Manufacturer A) or in double PE bags in card board drums (Manufacturer B). The documentation is in line with the current CEPs.

Drug Product

The drug product is effervescent tablets containing 600 mg acetylcysteine as drug substance, and packaged in well-known aluminium based blister material. The excipients are typical for this type of dosage form and well known. The manufacturing process including flow chart is adequately documented. The provided process validation data are sufficient.

Each of the excipients except the flavour complies with respective Ph. Eur. monographs. Information given for the lemon flavour is sufficient.

The release and shelf life specifications are appropriate for this pharmaceutical dosage form.

The analytical control methods are adequately described and the validation is in general in accordance to the current ICH requirements. The batch analysis data are given showing compliance with set specifications and high batch-to-batch consistency.

The chosen packaging system is well-known aluminium and paper based blister material. The stability study is in line with the current ICH requirements. Special storage conditions are not necessary. The shelf life of 3 years is granted.

• III.2 Non-clinical aspects

Pharmacology, Pharmacokinetics, Toxicology

The present application is a bibliographic application referring to Art 10 a Dir 2001/83/EC. Art. 10a applications are “full dossier applications”, i.e. for nonclinical pharmacology, pharmacokinetics and toxicology each aspect defined in the “Common Technical Document” (ICH M4) has to be covered by adequate published data or their absence scientifically justified, based upon the criteria of ‘well established medicinal use’ as outlined in Annex 1 to Directive 2001/83/EC as amended.

The applicant has performed a comprehensive literature search for nonclinical effects of N-acetylcysteine (NAC) and the results of this data search have been summarized.

Overall, the nonclinical data for NAC as presented do not fully comply with the current regulatory requirements. ‘Deficits exist e.g. with regard to the following aspects:

• – it has not been clarified whether the NAC preparations used in the cited nonclinical studies were similar in composition to the product currently submitted for marketing authorisation

• – the GLP status of the cites studies is unclear/the studies have not been performed according to GLP

• – the clinical relevance of the data provided for primary pharmacology of NAC has not been (convincingly) shown

• – safety pharmacology data (including in vitro and in vivo data on cardiac action potential and QT duration) are missing

• – the pharmacokinetics (ADME) of NAC has been incompletely evaluated, toxicokinetic data are not available

• – the chronic toxicity of NAC has been incompletely evaluated [in just one species (rat)]

• – the genotoxic potential of NAC has been incompletely evaluated (in vitro and in vivo data on

the clastogenic potential are missing)

Therefore, from a nonclinical point of view, a “well established use” of NAC cannot be deduced on basis of the submitted nonclinical data.

However, it is acknowledged that, based on the wide-spread therapeutic use of NAC, the available human data may supersede the aforementioned deficits. The further regulatory assessment should therefore focus on the data submitted for efficacy and safety of NAC administration to humans (see III.3 Clinical Aspects).

Environmental Risk Assessment (ERA)

According to the guideline on the environmental risk assessment of medicinal products for human use “Vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates and lipids are exempted because they are unlikely to result in significant risk to the environment.” Since cysteine is a naturally occurring amino acid the approach of the applicant can be followed and it can be concluded that the active ingredient acetylcysteine will not pose a significant risk to the environment. Therefore the submission of an ERA is deemed not necessary.

• III.3 Clinical aspects

Pharmacokinetics

Absorption

Following oral administration, acetylcysteine is rapidly absorbed; however bioavailability is low (approximately 10%) due to extensive first-pass metabolism in the small intestine and liver. Following a single 600 mg oral dose of acetylcysteine in humans, peak plasma concentrations of 4.6 μM have been reported at 1 hour, with plasma concentrations rapidly declining to 2.5 μM at 90 minutes (plasma half-life approximately 2 hours). Virtually no acetylcysteine is detectable 10–12 hours post-administration.

Biotransformation

Acetylcysteine undergoes rapid deacetylation in vivo to yield the pharmacologically active substance cysteine, thereby entering the normal cysteine metabolic pathway. Acetylcysteine also undergoes oxidation to yield a variety of metabolites including diacetylcysteine. Hepatic impairment leads to a prolonged plasma half-life of up to 8 hours.

Acetylcysteine may be present in the plasma as the parent compound or as various oxidised metabolites, including N-acetylcysteine, and cysteine and either free or bound to plasma proteins, by labile disulphide bonds, or as a fraction incorporated into protein peptide chains. Following administration of a 100 mg oral dose of acetylcysteine, 48% was measurable in lung tissue.

Protein binding of acetylcysteine is approximately 50%.

Elimination

Following oral administration of acetylcysteine, excretion is almost exclusively renal (22% – 30%), predominately in the form of inorganic sulphates, with only 3% excreted in the faeces. Total Body Clearance in healthy subjects is 6.5 L/hour. The mean terminal half-life is approximately 6 hours.

Pharmacokinetics in special patient groups

In a study (Nolin TD, Ouseph R, Himmelfarb J, McMenamin ME, Ward RA. Multiple- dose pharmacokinetics and pharmacodynamics of N-acetylcysteine in patients with end-stage renal disease. Clin J Am Soc Nephrol 2010 Sep;5(9):1588–94) with a multiple dose regimen the authors presumed that non-renal clearance of NAC by enzymes or drug transporters may be altered by kidney disease.

The authors from another PK study (with NAC 600 mg iv) concluded that further studies are necessary to determine the optimal dosage regime in cirrhotic patients.

Pharmacodynamics

Pharmacothera­peutic group : Mucolytics, ATC code: R05CB01

Mechanism of action and pharmacodynamic effects

Acetylcysteine depolymerises mucus in vitro by breaking the disulphide bonds between macromolecules present in the mucus, thereby reducing mucosal viscosity. Acetylcysteine activates the ciliated epithelium. In conclusion this facilitates expectoration and improves mucociliary clearance. Acetylcysteine acts as an antioxidant and is a precursor of cysteine, the rate-limiting amino-acid for glutathione synthesis in most tissues.

Clinical efficacy and safety

The applicant has substituted the required clinical efficacy studies from literature with the relevant publications. The applicant claims that the efficacy of acetylcysteine is well known and proposes new the following wording for the indication “in adults as a mucolytic agent for the treatment of respiratory tract diseases in which a reduction in bronchial secretion viscosity is required to facilitate expectoration“.

For this indication wording clinical efficacy and safety can be assumed from the literature and it can be assessed as POM status.

The applicant justified that the excipients will not affect absorption of acetylcysteine so that an additional supportive BE study as bridging will not be necessary.

Bridge to the literature data

This is a bibliographic application for Acetylcysteine 600 mg effervescent tablets, submitted under Article 10(a), Directive 2001/83/EC. A 600 mg effervescent tablet preparation of acetylcysteine was first licensed in the European Union on 8 August 1995 (Fluimucil Hustenlöser akut 600 mg Effervescent Tablets, licensed to Zambon GmbH, Germany). However, different acetylcysteine preparations were used in the literature provided for this EU application.

N-acetylcysteine has a high solubility and high permeability; therefore, it is classified as a BCS class I drug substance. Acetylcysteine 600 mg effervescent tablets typically dissolve within 80 seconds, yielding clear oral solutions. The product contains acetylcysteine in the same concentration as e.g. Fluimucil 600 mg effervescent tablets. The justification to waive in-vivo comparative bioavailability study given by the applicant is plausible, especially since acetylcysteine demonstrates almost complete absorption. It is agreed that the only difference in excipients compared to Fluimucil 600 mg effervescent tablets that may affect gastrointestinal transit is mannitol and sorbitol. The total content of mannitol of one single dose of ACC 600 mg effervescent tablets (89.62 mg) is by power of 10 lower than the findings of Adkin (Adkin 1995). Furthermore, the total amount of sorbitol ingested with single doses of ACC 600 mg effervescent tablets (0.52 mg) is also much lower than the laxative dose (> 5g) and is not likely to cause any problems in terms of the bioavailability or tolerability of the active substance ACC. Due to the low amount of mannitol and sorbitol the influence of these excipients on gastric emptying is considered negligible. Furthermore, other ACC containing products contain either mannitol, sorbitol or both in similar amounts as highlighted by the applicant. Overall, an exemption from in-vivo comparative bioavailability is acceptable, in accordance with the Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/9­8/Rev1.

Legal Status

In DE: POM

User Testing

Bridging Report:

This report bridges from the proposed PIL for Acetylcystein Stirling Anglian 600 mg Brausetabletten to the PIL User Test Report for Aceo 600mg effervescent tablets, to demonstrate that the proposed PIL meets the requirements of article 59 (3) without the need for user testing.

Conclusion

The legibility, clearness, accessibility, easy to read and easy to understand characteristics of the package leaflet have been demonstrated by appropriate user consultation on the user tested Aceo 600mg effervescent tablets version of the leaflet he package leaflet evaluation and study were in accordance with:

• EC “A Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human use" Revision 1 (12 January 2009).
• EC „Guidance concerning consultation with target patient groups for the Package Leaflet“ (May 2006)
• MHRA „Guidance on User Testing of Patient Information LeafIets“ (2005)

This concluded that the package leaflet complied with Article 59(3) of Directive 2001/83/EC which requires the package leaflet ‘to reflect the results of consultations with target patient groups to ensure that it is legible, clear and easy to use’.

The user tested PIL for Aceo 600mg effervescent tablets is identical to the proposed PIL for Acetylcystein Stirling Anglian 600 mg Brausetabletten in terms of:

• Font and font size
• Headings and sub-headings including consistency of placement
• PIL dimensions, portrait format
• Use of colour and choice of colour
• Style of writing and language used
• Layout of critical safety sections of the PIL

The text of the user tested PIL for Aceo 600mg effervescent tablets is identical to proposed PIL for Acetylcystein Stirling Anglian 600 mg Brausetabletten , with the exception of the single change. This additional text introduces 47 words as a single statement.

Care has been taken to use patient friendly language and explanations in this text.

On the basis of the above it can be concluded that the user consultation carried out for the Aceo 600mg effervescent tablets version of the package leaflet demonstrates that the proposed PIL for Acetylcystein Stirling Anglian 600 mg Brausetabletten meets the requirements of article 59(3) of Council Directive 2001/83/EC.

Summary Pharmacovigilance system

The Applicant has submitted a signed Summary of the Applicant's and/or 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 a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.

Safety specification

According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.

Pharmacovigilance Plan

Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.

Risk minimisation measures

Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.

Summary of the RMP

The submitted Risk Management Plan is considered acceptable.

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:

• – At the request of the RMS;

• – Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.

If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.

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.
• For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

• IV. BENEFIT RISK ASSESSMENT