Summary Public Assessment Report. non-generics. (Acetylcysteine) PT/H/873/001/MR

Transcription

1 Summary Public Assessment Report non-generics Acetilcisteína Friulchem (Acetylcysteine) Summary PAR non-generics 1/8 Acetilcisteína Friulchem

2 Acetilcisteína Friulchem Acetylcysteine 1200 mg effervescent tablets Summary Public Assessment Report non-generics This is a summary of the public assessment report (PAR) for Acetilcisteína Friulchem It explains how Acetilcisteína Friulchem was assessed and its authorisation recommended as well as its conditions of use. It is not intended to provide practical advice on how to use Acetilcisteína Friulchem For practical information about using Acetilcisteína Friulchem, patients should read the package leaflet or contact their doctor or pharmacist. Acetilcisteína Friulchem is a medicine with well-established use. This means that the medicinal use of the active substance of Acetilcisteína Friulchem is well established in the European Union for at least ten years, with recognised efficacy and an acceptable level of safety. Acetilcisteína Friulchem is used as secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus. How is Acetilcisteína Friulchem used? The pharmaceutical form of Acetilcisteína Friulchem is effervescent tablets and the route of administration is oral. Please read section 3 of the PL for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Posology for adults: During acute phase: A half effervescent tablet of Acetilcisteína Friulchem (600 mg acetylcysteine) once a day, during 4 to 5 days. The regular single and maximum dose is 600 mg acetylcysteine (1/2 tablet) per day. Use in children Acetilcisteína Friulchem is indicated in adults. Acetilcisteína Friulchem must not be used in children. Other appropriate pharmaceutical forms are available. Use in elderly people: Elderly people can use this medicine. It is recommended to use precaution in case of gastroduodenal ulcer Way of administration: Dissolve the half tablet (600 mg acetylcysteine) in a glass of water. Check that it is completely dissolved and drink immediately. A slight smell of sulphur is peculiar to Acetylcysteine. Summary PAR non-generics 2/8 Acetilcisteína Friulchem

3 It is recommended to increase water intake during the treatment with acetylcysteine because it supports the mucolytic effect. The medicine can only be obtained with a prescription. What benefits of Acetilcisteína Friulchem have been shown in studies? As Acetylcysteine is a well-known substance, and is used as secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus. is well established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of Acetylcysteine is use as secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus. What are the possible side effects from Acetilcisteína Friulchem? For the full list of all side effects reported with Acetilcisteína Friulchem see section 4 of the package leaflet. For the full list of restrictions, see the package leaflet. Why is Acetilcisteína Friulchem approved? The INFARMED, I.P. decided that Acetilcisteína Friulchem benefits are greater than its risks and recommended that it be approved for use. A risk management plan dated 23 August 2013, version 1.0, has been developed to ensure that Acetilcisteína Friulchem is used as safely as possible. Based on this plan, safety information has been included in the summary of product characteristics and the package leaflet for Acetilcisteína Friulchem, including the appropriate precautions to be followed by healthcare professionals and patients. Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/ reviewed continuously as well. Other information about AcetilcisteínaFriulchem The marketing authorisation for Acetilcisteína Friulchem was granted on of issue of the Marketing Authorisation. The full PAR for Acetilcisteína Friulchem can be found on the website For more information about treatment with Acetilcisteína Friulchem, read the package leaflet or contact your doctor or pharmacist. Summary PAR non-generics 3/8 Acetilcisteína Friulchem

4 Public Assessment Report Scientific discussion Acetilcisteína Friulchem (Acetylcysteine) This module reflects the scientific discussion for the approval of Acetilcisteína Friulchem The procedure was finalised at For information on changes after this date please refer to the module Update. Summary PAR non-generics 4/8 Acetilcisteína Friulchem

5 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have agreed in recognized a marketing authorisation for Acetilcisteína Friulchem1200 mg effervescent tablets, from FRIULCHEM S.p.A. Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals. The efficacy and safety of use of the drug as a mucolytic is well known for nearly 40 years. Acetylcysteine is a mucolytic, with mucokinetic actions including expectorant, bronchorrheic and mucoregulatory contributions. The product is indicated for Secretolytic therapy in acute and chronic bronchopulmonary diseases accompanied by impaired formation and transport of mucus. Posology A half of the effervescent tablet of Acetilcisteína Friulchem a day (600 mg acetylcysteine), not longer than for 4-5 days. The regular single and maximum dose is 600 mg acetylcysteine per day Method of administration Acetilcisteína Friulchem should be taken after a meal. The half effervescent tablet (600 mg acetylcysteine) is dissolved in a glass of water. After dissolution of the half effervescent tablet the solution should be drunk immediately. It is recommended to increase water intake during the treatment with acetylcysteine because it supports the mucolytic effect. The marketing authorisation has been granted pursuant to Article 10a well established use application of Directive 2001/83/EC on Portugal was the Reference Member State in this Mutual Recognition Procedure and the concerned member state was Germany. II. QUALITY ASPECTS II.1 Introduction The pharmaceutical form of Acetilcisteína Friulchem is effervescent tablets and the route of administration is oral. The excipients are anhydrous citric acid, ascorbic acid, sodium citrate dihydrate, sodium cyclamate, saccharin sodium, mannitol, sodium hydrogen carbonate, anhydrous sodium carbonate, anhydrous lactose, blackberry flavour. Acetilcisteína Friulchem is available in boxes of 12, 20, 24, 48 effervescent tablets, with thermoselaed strips of two tablets each or boxes of 20, 25, 50 (2x25) effervescent tablets in PP tube containers with PE cap with desiccant. II.2 Drug Substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Acetilcisteína Friulchem are of sufficient quality in view of the present European regulatory requirements. Summary PAR non-generics 5/8 Acetilcisteína Friulchem

6 The control tests and specifications for drug substance product are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 5 years is justified. II.3 Medicinal Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on 4 batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The proposed shelf-life of 36 months when stored below 30ºC for the drug product packed in polypropylene tubes closed with polyethylene stoppers containing desiccant and into laminated aluminium-paper-foil strips is considered acceptable. After the first opening, a shelf-life of 12 months is acceptable. III. NON-CLINICAL ASPECTS The antioxidant and mucolytic effects of NAC are mainly mediated through the free thiol (sulfhydryl) group interactions with the electrophilic groups of ROS. In addition, an indirect antioxidant effect related to NAC role as a GSH precursor has also been mentioned. The proof of concept has further been supported by the well-established clinical use. Pharmacology Data from in vitro studies and animal models of diseases characterized by decreased GSH levels or oxidative stress have been reviewed and focused on the effects of NAC in some biological and pathological processes with particular emphasis on the molecular mechanisms of its action. These results suggest the potential therapeutic use of NAC in different fields like cancer, inflammation, liver and cardiovascular diseases. The lack of data from the regular safety pharmacology studies, according to the current approved guidelines, is acceptable due to the extensive clinical data. The lack of pharmacodynamic drug interation studies is acceptable. Pharmacokinetics Pharmacokinetic studies showed extensive absorption and distribution and rapid elimination in all animal species examined. Taking into consideration the nature of the active substance (NAC is the N- acetyl derivative of the naturally occurring amino acid L-cysteine) and pharmacokinetics data available from the well established clinical use, it can be considered that pre-clinical data are superseded by clinical use and no additional non-clinical will be required. Toxicology According to LD50 established by oral and intravenous administration, NAC shown a low acute toxicity profile. No significant adverse events were reported with subacute and chronic administration of NAC. However, the safety margins from repeat dose studies can t be established as the correspondent toxicokinetics data is not available. The lack of this information is not considered a matter for objection, taking into account the extensive and well established clinical use NAC. No adverse effects on fertility and embryo-fetal development were reported. Reproductive toxicity studies/segment III have not been included. No mutagenic potential in vitro has been observed. The results of these studies provide no basis for a complete assessment of the genotoxic risk according to the current guidelines. The lack of the required genotoxicity set of studies will be accepted as the NAC preclinical development has been performed around 50 years ago and no additional genotoxicity findings have been described. No carcinogenicity potential has been observed for NAC. Summary PAR non-generics 6/8 Acetilcisteína Friulchem

7 Environmental Risk Assessment (ERA) The active ingredient NAC has not environmental impact. IV. CLINICAL ASPECTS Pharmacokinetics N-Acetylcysteine has a linear and dose-dependent pharmacokinetics. In a study conducted in healthy subjects after administration of oral solutions of mg of acetylcysteine has been observed increasing C max and t max levels and dose-dependent bioavailability. The administration of 1200 mg solutions produces C max concentrations more elevated than after administration of 600 mg and t max appears more prolonged and the bioavailability more elevated. Pharmacodynamics Acetylcysteine plays an essential role in maintaining appropriate levels of GSH by exerting a cytoprotective agent against the adverse such as paracetamol at high doses, which degrade the GSH and are cytotoxic. By being antioxidant, acetylcysteine has a cytoprotective action on the respiratory tract compared to toxic phenomena that are triggered by the release of free radicals oxidizing diverse etiology. Acetylcysteine acts as a precursor for the synthesis of glutathione and, therefore, maintains cellular glutathione at a level sufficient to inactivate NAPQI. This is thought to be the main mechanism by which acetylcysteine acts in the early stages of paracetamol toxicity. Clinical efficacy To support the application, the applicant has submitted a clinical overview with a literature review. The efficacy of Acetylcysteine for self-limited respiratory disease in children and in acute lung injury (including acute respiratory distress syndrome) in adults has a limited evidence. Clinical Guidelines as GOLD mentioned that mucolytic agents could reduce: the frequency of acute exacerbations of chronic bronchitis, disability days and antibiotic use. There are other indications where Acetylcysteine is considered: an orphan drug in the treatment of Interstitial Pneumonitis and as the antidote of choice in treating paracetamol-induced hepatotoxicity. Clinical safety The paediatric safety profile could be considered because this mucolytic has been prescribed for selflimiting diseases. The safety in children younger than two years was not established. Based on the literature and post-marketing data N_Acetylcysteine has a favourable safety profile for adults and children older than two years old. Risk Management Plan The MAH has submitted a risk management plan dated 23 August 2013, version 1.0., 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 Acetilcisteína Friulchem. V. USER CONSULTATION 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 language used for the purpose of user testing the PIL was Portuguese The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use. Summary PAR non-generics 7/8 Acetilcisteína Friulchem

8 VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Based on the review of the data on quality, safety and efficacy, the INFARMED, I.P. considers that the application for Acetilcisteína Friulchem, 1200 mg, Effervescent tablets, is approvable. Summary PAR non-generics 8/8 Acetilcisteína Friulchem