Public Assessment Report. Scientific discussion. Acetylsalicylzuur Disphar 500 mg and 1000 mg, oral powder. (acetylsalicylic acid)

Transcription

1 Public Assessment Report Scientific discussion Acetylsalicylzuur Disphar 500 mg and 1000 mg, oral powder (acetylsalicylic acid) NL/H/3464/ /DC Date: 21 June 2017 This module reflects the scientific discussion for the approval of Acetylsalicylzuur Disphar 500 mg and 1000 mg, oral powder. The procedure was finalised on 8 March For information on changes after this date please refer to the steps taken after finalisation at the end of this PAR.

2 List of abbreviations C CEP CMD(h) CMS EDQM ERA ICH MAH OTC Ph.Eur. PL RH RMP SmPC TSE Certificate of Suitability to the monographs of the European Pharmacopoeia Coordination group for Mutual recognition and Decentralised procedure for human medicinal products Concerned Member State European Directorate for the Quality of Medicines Environmental Risk Assessment International Conference of Harmonisation Marketing Authorisation Holder Over-the-counter European Pharmacopoeia Package Leaflet Relative Humidity Risk Management Plan Summary of Product Characteristics Transmissible Spongiform Encephalopathy 2/10

3 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Acetylsalicylzuur Disphar 500 mg and 1000 mg, oral powder from Disphar International B.V. The product is indicated for: mild to moderate pain fever A comprehensive description of the indications and posology is given in the SmPC. This decentralised procedure concerns a generic application claiming essential similarity with the innovator product Aspirin Effect 500 mg granulate which has been registered in Germany by Bayer Vital GmbH since 13 May The reference medicinal product in the Netherlands is Aspirin 500 mg, granulate (NL License RVG 28834) which has been registered by Bayer B.V. since 11 July The concerned member state (CMS) involved in this procedure was Germany. The marketing authorisation for the 500 mg strength has been granted pursuant to Article 10(1) of Directive 2001/83/EC (generic medicinal product). For the 1000 mg strength the legal base is Article 10(3) of Directive 2001/83/EC (hybrid medicinal product), as this strength is newly introduced and deviates from the regular 500 mg acetylsalicylic acid formulations that are available on the EU market in the over-the-counter (OTC) setting. However, the 1000 mg strength falls within the well-established regular dose range for the use in mild-moderate pain and fever of mg 3-4 times daily. II. QUALITY ASPECTS II.1 Introduction Acetylsalicylzuur Disphar is a white oral powder. The powder is packed in PET/aluminium/LDPE sachets. Each sachet contains as active substance 500 mg or 1000 mg of acetylsalicylic acid. The excipients are: mannitol (E421), anhydrous citric acid (E330), aspartame (E951), lemon flavour and maltodextrin. The two strengths are dose proportional. II.2 Drug Substance The active substance is acetylsalicylic acid, an established active substance described in the European Pharmacopoeia (Ph.Eur.). The active substance is a white or almost white, crystalline powder or colourless crystal. It is slightly soluble in water and soluble in ethanol (96%). Its pka is 3.5 at 25 C. Two crystal structures for acetylsalicylic acid are known. Form I is used for the current product. 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 Ph.Eur. 3/10

4 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 additional tests as mentioned in the CEP. Batch analytical data demonstrating compliance with the drug substance specification have been provided for six commercial scale batches. Stability of drug substance Stability data on the active substance have been provided for three commercial scale batches stored at 25 C/60% RH (36 months) and 40 C/75% RH (6 months). The substance is stable at both 25 C/60% RH and 40 C/75% RH. A retest period of 36 months in the commercial packaging configurations is justified without specific storage condition. II.3 Medicinal Product Pharmaceutical development The product is an established pharmaceutical form and its development is adequately described in accordance with the relevant European guidelines. The choice of the excipients justified and their functions explained. The safety of lemon flavour has been justified and the taste of the product has been optimised. The choices for the excipients and the packaging are justified in relation to the innovator. The manufacturing process was selected, optimised and scaled-up to commercial scale. The 1000 mg strength is dose-proportional to the 500 mg strength. The manufacture and composition of the batches used in the bioequivalence study are identical to the product intended to be marketed. Dissolution data at various ph values on the reference batch and the test batch used in the bioequivalence study have been included as well as dissolution data of both strengths to obtain a biowaiver of strength. The provided dissolution data support the requested biowaiver for the 1000 mg strength. Manufacturing process The method of manufacture for the drug product is seen as a standard process involving only sieving and mixing to obtain a common blend. Subsequently, an appropriate amount of the blend is filled in sachets to obtain either the 500 mg strength or the 1000 mg strength. The manufacturing process has been validated according to relevant European/ICH guidelines. Process validation data on the product have been presented for four commercial scale batches (two for each strength) batches in accordance with the relevant European guidelines. Control of excipients The pharmacopoeial excipients all comply with the Ph.Eur. The non-pharmacopoeial excipient lemon flavour is sufficiently characterised. The specifications are acceptable. Quality control of drug product The finished product specifications are adequate to control the relevant parameters for the dosage form. The specification includes tests for appearance, identity, assay, related substances, dissolution, uniformity of dosage units and microbiological quality. Release and shelf life specification limits are identical except for assay and related substances. Limits in the specification have been justified and are considered appropriate for adequate quality control of the product. Satisfactory validation data for the analytical methods have been provided. Batch analytical data from commercial scale batches (three of the 500 mg strength and two of the 1000 mg strength) from the proposed production site have been provided, demonstrating compliance with the specification. Stability of drug product Stability data have been provided for five commercial scale batches (three of the 500 mg strength and two of the 1000 mg strength) stored at 30 C/75% RH (18 months) and 40 C/75% RH ( 6 months). The conditions used in the stability studies are acceptable. The batches were packed in the intended trilaminate aluminium sachet. Both strengths remain within specifications during 18 months at 30 C/75% RH and 6 months at 40 C/75% RH, but an increase of the degradation product salicylic acid and total impurities is observed, as well as a decrease in assay values. The drug product is photostable. 4/10

5 Based on the stability data provided, a shelf-life of 24 months can be granted without additional storage conditions. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies There are no substances of ruminant animal origin present in the product nor have any been used in the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded. II.4 Discussion on chemical, pharmaceutical and biological aspects Based on the submitted dossier, the member states consider that Acetylsalicylzuur Disphar has a proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the active substance and finished product. No post-approval commitments were made. III. III.1 NON-CLINICAL ASPECTS Ecotoxicity/environmental risk assessment (ERA) Since Acetylsalicylzuur Disphar is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.2 Discussion on the non-clinical aspects This product is a generic formulation of Aspirin Effect 500 mg granules which is available on the European market. Reference is made to the preclinical data obtained with the innovator product. A non-clinical overview on the pharmacology, pharmacokinetics and toxicology has been provided, which is based on up-to-date and adequate scientific literature. The overview justifies why there is no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology data. Therefore, the member states agreed that no further non-clinical studies are required. IV. IV.1 CLINICAL ASPECTS Introduction Acetylsalicylic acid is a well-known active substance with established efficacy and tolerability. A clinical overview has been provided, which is based on scientific literature. The overview justifies why there is no need to generate additional clinical data. Therefore, the member states agreed that no further clinical studies are required. For this application, the MAH has submitted one bioequivalence study, which is discussed below. IV.2 Pharmacokinetics Bioequivalence study The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product Acetylsalicylzuur Disphar 500 mg (Disphar International B.V., The Netherlands) is compared with the pharmacokinetic profile of the reference product Aspirin Effect 500 mg (Bayer Vital GmbH, Germany). The choice of the reference product The choice of the reference product in the bioequivalence study has been justified. The formula and preparation of the bioequivalence batch is identical to the formula proposed for marketing. 5/10

6 Biowaiver A biowaiver for the 1000 mg is considered acceptable. All requirements for a waiver for the additional strength are met, in line with the Guideline on the investigation of bioequivalence: The two strengths are dose-proportional to each other and contain the same excipients. The products are manufactured by the same manufacturing process. The pharmacokinetics of acetylsalicylic acid is linear over the range mg. The obtained f 2 values at ph 1.2, 4.5 and 6.8 show that the dissolution profiles between the two strengths are similar. Additional dissolution studies have been performed to demonstrate this, due to high variation in dissolution of the reference product. Design A randomised, balanced, open-label, single-dose, two-period, two-sequence, two treatment, crossover comparative bioequivalence study was carried out under fasted conditions in 46 healthy subjects, aged years. Each subject received a single oral dose of two sachets (2x 500 mg) of one of the 2 acetylsalicylic acid formulations. The oral powder was orally administered without water after an overnight fast of at least 10 hours. There were 2 dosing periods, separated by a washout period of 12 days. Blood samples were collected pre-dose and at 5, 10, 15, 20, 25, 30, 35, 40, 45 minutes and then 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 hours after administration of the products. The design of the study is acceptable. The dose of 1000 mg (2x 500 mg) acetylsalicylic acid is within the normally accepted range for treatment with acetylsalicylic acid. The administration of the test drugs without water is agreed as it is recommended in the posology that the medicinal product should be poured directly into the mouth on the tongue and swallowed. The wash-out period of 12 days is long enough to prevent carry-over effects as this is 5 times the reported half-life of acetylsalicylic acid and salicylic acid ( hours and hours, respectively). The sampling schedule is considered adequate to estimate the pharmacokinetic parameters. The handling and processing of the plasma samples are according to standard procedures. Acetylsalicylic acid is metabolised to active metabolite salicylic acid. Bioequivalence is based on the parent molecule acetylsalicylic acid. This agreed as the C max of a parent compound is usually more sensitive to detect differences between formulations in absorption rate than C max of a metabolite. Analytical/statistical methods The analytical method has been adequately validated and is considered acceptable for analysis of the plasma samples. The methods used in this study for the pharmacokinetic calculations and statistical evaluation are considered acceptable. Results Two subjects withdrew after drug administration. The remaining 44 subjects completed both periods and were eligible for pharmacokinetic analysis. Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of acetylsalicylic acid under fasted conditions. Treatment N=44 Test Reference AUC 0-t ng.h/ml C max ng/ml 6/10 t max h t 1/2 h ± ± ± ± ± ± ± ± 0.13 *Ratio (90% CI) ( ) ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life CV coefficient of variation *ln-transformed values

7 Table 2. Supportive pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max (median, range)) of salicylic acid under fasted conditions. Treatment N=44 Test Reference AUC 0-t ng.h/ml C max ng/ml ± ± ± ± 9.21 t max h 2.5 ( ) 2.5 ( ) AUC 0-t area under the plasma concentration-time curve from time zero to t hours C max maximum plasma concentration t max time for maximum concentration t 1/2 half-life *ln-transformed values t 1/2 h 3.85 ± ± 1.23 Conclusion on bioequivalence study The 90% confidence intervals calculated for AUC 0-t and C max are within the bioequivalence acceptance range of Based on the submitted bioequivalence study Acetylsalicylzuur Disphar is considered bioequivalent with Aspirin Effect. Safety Two subjects experienced adverse events: one subject reported abdominal pain during study period II after receipt of test product and the second subject reported heart burn during period II after receipt of reference product. Both adverse events were mild in intensity and resolved with bed rest. The MEB has been assured that the bioequivalence study has been conducted in accordance with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC). IV.3 Clinical safety The 1000 mg strength is newly introduced, and deviates from the regular 500 mg acetylsalicylic acid formulations that are available on the EU market in the OTC setting. It is noted that this strength falls within the well-established regular dose range for the use in mild-moderate pain and fever of mg 3-4 times daily. However, the introduction of a new strength brings along that dosing errors may occur, if accidently two sachets and a double 1000 mg dose is taken. Moreover, it brings along a lack of flexibility and a potential risk of unnecessary overuse. The MAH has provided evidence from the literature that if a double dose of 1000 mg is accidently taken, this is still well below the acute intoxication threshold of g. Moreover, the MAH has summarised all measures to prevent unnecessary/incorrect use of the 1000 mg strength: The boxes and sachets will have a different appearance regarding colours and size. For the 1000 mg product, the pack size will be limited to 2 or 10 sachets. A warning has been included in the SmPC and Package Leaflet (PL) that undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. Maximum treatment duration is also mentioned and it is stated that for longer use a physician should be consulted. Separate PLs are provided for the 500 mg and 1000 mg strength. The complete dose recommendation (i.e mg 3-4 times a day) is mentioned in the PL of the 1000 mg strength On each 1000 mg sachet and on the outer packaging, a warning is printed not taking more than one sachet at a time with a maximum of 4 sachets a day. In addition to the above measures, the Board decided to limit the legal status of supply of the 1000 mg strength to UA, while the lower 500 mg strength has UAD/UA. IV.4 Risk Management Plan 7/10

8 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 Acetylsalicylzuur Disphar. Summary table of safety concerns as approved in RMP: Important identified risks Gastro-intestinal bleeding, ulceration, and perforations, including interactions with medication that can increase the risk of bleeding Renal toxicity Hypersensitivity reactions to acetylsalicylic acid Bone marrow toxicity due to interaction with methotrexate Severe skin reactions (Stevens-Johnson syndrome, epidermal necrolysis) Cardiovascular and cerebrovascular events (heart failure, MI and CVA) Use during pregnancy and lactation Medication Overuse Headache (MOH) Important potential risks Reye's syndrome in children <18 years of age Medication errors Missing information -- The member states agreed that routine pharmacovigilance activities and routine risk minimisation measures are sufficient for the risks and areas of missing information. IV.5 Discussion on the clinical aspects For this authorisation, reference is made to the clinical studies and experience with the innovator product Aspirin Effect. No new clinical studies were conducted. The MAH demonstrated through a bioequivalence study that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of this reference product. Risk management is adequately addressed. This generic medicinal product can be used instead of the reference product. V. USER CONSULTATION The PL 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. Two stages of testing were performed each involving a pilot test with 8 participants, followed by two rounds with 10 participants each. The questionnaire sufficiently addressed the key safety issues of acetyl salicylic acid and the format of the leaflet. The results show that the PL meets the criteria for readability as set out in the Guideline on the readability of the label and PL of medicinal products for human use. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION Acetylsalicylzuur Disphar 500 mg and 1000 mg, oral powder has a proven chemical-pharmaceutical quality. The 500 mg strength is a generic form of Aspirin Effect 500 mg; the 1000 mg strength is a hybrid form. Aspirin Effect is a well-known medicinal product with an established favourable efficacy and safety profile. Bioequivalence has been shown to be in compliance with the requirements of European guidance documents. The application was discussed in the Board meetings of 4 June 2015, 29 October 2015 and 4 February Questions were raised regarding quality aspects, the justification for a biowaiver, the risk of dosing errors and the potential risk of unnecessary overuse. The MAH adequately addressed 8/10

9 the quality concerns. Sufficient additional risk minimisation measures have been provided to ensure safe use of the 1000 mg formulation. Overall, the Board concluded that the benefit-risk balance for this medicinal product is positive. For the 500 mg strength the UAd/UA status has been granted. For the 1000 mg the legal status of supply is limited to UA. There was no discussion in the CMD(h). Agreement between member states was reached during a written procedure. The member states, on the basis of the data submitted, considered that essential similarity has been demonstrated for Acetylsalicylzuur Disphar with the reference product, and have therefore granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome on 4 July /10

10 STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE SUMMARY Scope Procedure number Type of modification Date of start of the procedure Date of end of the procedure Approval/ non approval Assessment report attached 10/10