Public Assessment Report Scientific discussion Aspirin (acetylsalicylic acid) Asp no: 20150618 Tis module reflects te scientific discussion for te approval of Aspirin. Te procedure was finalised on 20160609. For information on canges after tis date please refer to te module Update. Postadress/Postal address: P.O. Box 26, SE751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se Email: registrator@mpa.se Template version: 20160219
I. INTRODUCTION Bayer AB as applied for a marketing autorisation for Aspirin, 500 mg, granules. Te active substance acetylsalicylic acid is te same as in Aspirin, tablets, marketed by Bayer AB since 1935. For approved indications, see te Summary of Product Caracteristics. Te marketing autorisation as been granted pursuant to Article 8(3) of Directive 2001/83/EC. For recommendations to te marketing autorisation not falling under Article 21a/22 of Directive 2001/83 and conditions to te marketing autorisation pursuant to Article 21a or 22 of Directive 2001/83/EC to te marketing autorisation, please see section VI. II. II.1 QUALITY ASPECTS Drug Substance Te structure of te drug substance as been adequately proven and its pysicocemical properties are sufficiently described. Te manufacture of te drug substance as been adequately described and satisfactory specifications ave been provided for starting materials, reagents and solvents. Te drug substance specification includes relevant tests and te limits for impurities and degradation products ave been justified. Te analytical metods applied are suitably described and validated. Stability studies confirm te retest period. II.2 Medicinal Product Te medicinal product is formulated using excipients listed in section 6.1 in te Summary of Product Caracteristics. Te manufacturing process as been sufficiently described and critical steps identified. Te tests and limits in te specification are considered appropriate to control te quality of te finised product in relation to its intended purpose. Stability studies ave been performed and data presented support te self life and special precautions for storage claimed in te Summary of Product Caracteristics, sections 6.3 and 6.4. 2/9
III. NONCLINICAL ASPECTS No new nonclinical studies were submitted for tis application. Parmacodynamics, parmacokinetic and toxicological properties of acetylsalicylic acid are considered wellknown. Since Aspirin 500 mg coated tablets can be expected to result in similar systemic exposure and clinical safety profile as oter Aspirin products, te lack of additional studies is considered acceptable. III.1 Ecotoxicity/environmental risk assessment An Environmental Risk Assessment (ERA) in accordance wit te "Guideline on te Environmental Risk Assessment of Medicinal Products for Human Use" (CHMP/SWP /4447/00) was submitted. Overall, te environmental risk assessment sows no environmental concerns. It can be concluded tat acetylsalicylic acid is unlikely to represent a risk to te environment under te proposed conditions of use. IV. IV.1 CLINICAL ASPECTS Introduction IV.2 Parmacokinetics In order to demonstrate te release caracteristics of te new granule formulation and to bridge between te new formulation and previously approved formulations four bioavailability studies ave been conducted. Study PH28658 A randomised, 3way, singledose, crossover study to evaluate te relative bioavailability of Aspirin dry granules 500 mg and a new Aspirin tablet in comparison to te 500 mg Aspirin plain tablet. Te results demonstrate comparable AUC and Cmax for SA and comparable AUC for ASA following administration of Aspirin granules and tablet. Not unexpectedly te rate of absorption was sligtly faster for te granules resulting in an approx. 50% iger Cmax for ASA. Table 1. Parmacokinetic parameters (nontransformed values; geometric mean (CV%), tmax median, range) for ASA, n=17. Treatment AUC 0 Granules (Test A) AUC norm kg*/l,norm kg/l 4.97 (17.4) 0.790 (16.8) 5.34 (24.3) 0.850 (21.6) 0.333 0.3331 Tablet (Reference C) 4.25 (44.3) 0.676 (43.0) 3.63 (74.0) 0.577 (73.0) 0.5 0.3332 *Ratio (90% CI) 1.18 (1.031.34) *calculated based on lntransformed data 1.46 (1.131.87) 3/9
Table 2. Parmacokinetic parameters (nontransformed values; geometric mean (CV%), median, range) for SA, n=17. Treatment AUC 0 AUC norm,norm Granules (Test A) kg*/l 106 (27.8) 22.0 (23.5) 21.5 (19.0) 4.46 (14.8) 1.5 0.8332 kg/l Tablet (Reference C) 107 (26.7) 22.2 (23.4) 20.1 (22.4) 4.18 (20.1) 2 0.8333.06 *Ratio (90% CI) 0.99 (0.931.07) *calculated based on lntransformed data 1.07 (0.981.16) Study PH3110 A randomised, 2way, singledose, crossover study to evaluate te relative bioavailability of Aspirin granules 2x500 mg and Aspirin effervescent tablet 2x500 mg. Wit respect to ASA te total exposure (AUC) was similar but te rate of absorption slower resulting in 45% lower Cmax after administration of te granules compared to te effervescent tablet. Tis is expected since te effervescent tablet is in solution at time of administration. For SA bot AUC and Cmax were similar wit 90% CI of te T/Rratio witin te conventional bioequivalence acceptance limits after administration of granules in comparison to effervescent tablets. Table 3. Parmacokinetic parameters (nontransformed values; geometric mean ± SD, median, range) for ASA, n=12. Treatment AUC 0 Granules (Test) 9.44 ± 1.26 9.61 ± 1.27 0.42 0.170.67 Effervescent tablet (Reference) 9.66 ± 1.19 17.2 ± 1.31 0.33 0.170.50 *Ratio (90% CI) 0.9776 (0.89381.0692) *calculated based on lntransformed data 0.5598 (0.48560.6452) Table 4. Parmacokinetic parameters (nontransformed values; geometric mean ± SD, median, range) for SA, n=12. Treatment AUC 0 Granules (Test) 262 ± 1.26 41.3 ± 1.20 1.50 0.673.00 Effervescent tablet (Reference) 259 ± 1.21 46.8 ± 1.14 0.83 0.331.00 *Ratio (90% CI) 1.0131 (0.92751.1065) *calculated based on lntransformed data 0.8819 (0.84480.9207) 4/9
Study PH32192 A randomised, 2way, singledose, crossover study to evaluate te relative bioavailability of Aspirin granules 500 mg given wit and witout water. For SA te 90% CI of te T/Rratio for AUC and Cmax were witin te conventional bioequivalence acceptance limits of 80125% and also for ASA AUC. ASA Cmax was sligtly lower after administration witout water. Tis is unlikely to be of any clinical relevance. Te proposed metod of administration in te SmPC: Te granules sould be poured directly on te tongue and allowed to dissolve in te saliva before swallowing. A little fluid can be taken afterwards, is supported. Table 5. Parmacokinetic parameters (nontransformed values; geometric mean ± SD, median, range) for ASA, n=23. Treatment AUC 0 Witout water 5.14 ± 1.19 4.02 ± 1.47 0.667 0.1671.50 Wit water 4.83 ± 1.22 4.68 ± 1.38 0.500 0.3302.00 *Ratio (90% CI) 1.0619 (1.00261.1247) 0.8582 (0.76320.9650) *calculated based on lntransformed data Table 6. Parmacokinetic parameters (nontransformed values; geometric mean ± SD, median, range) for SA, n=23. Treatment AUC 0 Witout water 108 ± 1.29 21.5 ± 1.24 1.50 0.8343.00 Wit water 111 ± 1.28 21.9 ± 1.20 1.50 1.503.00 *Ratio (90% CI) 0.9715 (0.92101.0248) 0.9794 (0.91731.0456) *calculated based on lntransformed data Voelker&Hammer 2012; study 1 A randomised, singledose, crossover study to evaluate PK of 500 mg fastrelease tablet wit 500 mg granules and 500 mg Aspirin tablets. Te full study report wic forms te ground for te publised study by Voelker and Hammer (2012) as not been provided and a detailed assessment tus not possible. Te general study design does owever seem to be in line wit te oter studies described in tis report. Te results are in accordance wit study PH28658 wit comparable AUC and Cmax for SA and comparable AUC for ASA and wit approx. 50% iger Cmax for ASA following administration of Aspirin granules compared to te plain tablet. Overall conclusions on parmacokinetics Te overall exposure of ASA and SA after administration of te new Aspirin granule formulation was similar compared to bot Aspirin conventional tablets and Aspirin effervescent tablets. Te rate of absorption of ASA from te granule formulation was 5/9
somewere in between te conventional tablet and te effervescent tablet resulting in Cmax values iger tan for te tablet but lower tan for te effervescent tablet. Te exposure of ASA and SA was similar wen te granules were administered wit and witout water. ASA Cmax was sligtly lower after administration witout water. Tis is unlikely to be of any clinical relevance. In conclusion, te product is considered to be sufficiently similar to te already approved formulations (tablet and effervescent tablet) to be approvable based on parmacokinetic data alone. IV.3 Parmacodynamics ASA belongs to te group of acidic nonsteroidal antiinflammatories (NSAIDs), and as been in medical use for over 100 years. ASA exerts its analgetic, antiinflammatory and antipyretic effect by inibition of cyclooxygenase (COX)catalysed conversion of aracidonic acid into prostaglandins, prostacyclin and tromboxane. IV.4 Clinical efficacy Te submitted literature data provides an overview of te current knowledge of te effects of ASA. Te available data supports te use of ASA for te applied terapeutic indications, i.e. te symptomatic relief of eadace, menstrual pain, tootace, muscular and joint pain and fever associated wit infections and common cold. IV.5 Clinical safety Te use of ASA for te applied terapeutic indications, i.e. te symptomatic relief of eadace, menstrual pain, tootace, muscular and joint pain and fever associated wit infections and common cold, is wellestablised. Te vast amount of patients tat ave been exposed to ASA since it was first marketed provide a substantial base for te assessment of te drug s safety. Safety of ASA as also been torougly explored in a large amount of publised studies. Te Applicant presents an adequate and relevant overview of adverse events, safety in special populations and interactions involving ASA. Overall, literature data suggests tat ASA is welltolerated wen used in line wit te proposed posology. Te safety profile is wellknown and no new safety concerns can be identified. IV.6 Risk Management Plans Te MAH as submitted a risk management plan, in accordance wit te requirements of Directive 2001/83/EC as amended, describing te parmacovigilance activities and interventions designed to identify, caracterise, prevent or minimise risks relating to Aspirin. Safety specification Summary table of safety concerns as approved in RMP Important identified risks gastrointestinal disorders (ulcer, perforation and bleeding) bleeding ypersensitivity reactions disturbance in renal function omeostasis in patients wit renal, epatic or cardiac insufficiency emolysis in patients wit G6PD deficiency interaction wit drugs igly bound to plasma proteins and drugs wit addtive toxicity potential use in tird trimester of pregnancy may expose o te foetus to cardiopulmonary toxicity (wit premature 6/9
Important potential risks Important missing information closure of of te ductus arteriosus and pulmonary ypertension), and renal dysfunction. o te moter and cild to: possible prolongation of bleeding time due to an anti aggregating effect on te platelets wic may occur even after very low doses inibition of uterine contractions resulting in delayed or prolonged labour. Reye s syndrome None Parmacovigilance Plan Routine parmacovigilance is suggested and no additional parmacovigilance activities are proposed by te applicant, wic is endorsed. Risk minimisation measures Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by te applicant, wic is endorsed. Summary of te Risk Minimisation Plan Te MAH proposed safety specification includes relevant safety issues, owever, one can debate if all of te proposed risks are considered as important in te RMP perpsective. However, wit a PSUSA soon coming up (DLP 1 Febr 2016) tere will be an opportunity to discuss witin te PRAC and armonize te safety concerns to be followed, tat is te risks defined in a RMP. Terefore is te proposed safety spcification acceptable for te time beeing. Te RMP is approved Te MAH sall perform te required parmacovigilance activities and interventions detailed in te agreed RMP presented in Module 1.8.2 of te Marketing Autorisation and any agreed subsequent updates of te RMP. An updated RMP sould be submitted: At te request of te RMS; Wenever te risk management system is modified, especially as te result of new information being received tat may lead to a significant cange to te benefit/risk profile or as te result of an important (parmacovigilance or risk minimisation) milestone being reaced. If te dates for submission of a PSUR and te update of a RMP coincide, tey can be submitted at te same time, but via different procedures. V. USER CONSULTATION A user consultation wit target patient groups on te package information leaflet (PIL) as been performed on te basis of a bridging report making reference to Asproflas 500 mg coated tablet (FR/H/0482/001/DC) for te content and reference to Aspirin Plus C 400 mg/240 mg effervescent tablet regarding layout (assessed and accepted by German BfArM in 29 June 2009). Te bridging report submitted by te applicant as been found acceptable. 7/9
VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION ASA is a wellestablised nonsteroid antiinflammatory agent wit analgetic, antipyretic and antiinflammatory properties wic as been in medical use for over 100 years. Its mecanism of action is well understood, as it is one of te most widely studied drugs ever. Te submitted literature data provides an overview of te current knowledge of te effects of ASA. Te available data supports te use of ASA for te applied terapeutic indications, i.e. te symptomatic relief of eadace, menstrual pain, tootace, muscular and joint pain and fever associated wit infections and common cold. Te Applicant presents an adequate and relevant overview of te safety profile for ASA. Overall, literature data suggests tat ASA is welltolerated wen used in line wit te proposed posology. Te safety profile is wellknown and no new safety concerns can be identified. Te overall exposure of ASA and SA after administration of te new Aspirin granule formulation was similar compared to bot Aspirin conventional tablets and Aspirin effervescent tablets. Te rate of absorption of ASA from te granule formulation was somewere in between te conventional tablet and te effervescent tablet resulting in Cmax values iger tan for te tablet but lower tan for te effervescent tablet. In conclusion, te product is considered to be sufficiently similar to te already approved formulations (tablet and effervescent tablet) to be approvable based on parmacokinetic data alone. List of recommendations not falling under Article 21a/22 of Directive 2001/83 in case of a positive benefit risk assessment N/A List of conditions pursuant to Article 21a or 22 of Directive 2001/83/EC N/A VII. APPROVAL Aspirin, 500 mg, granules was approved in te national procedure on 20160609. 8/9
Public Assessment Report Update Procedure number* Scope Product Information affected Date of end of procedure Approval/ non approval Summary/ Justification for refuse *Only procedure qualifier, cronological number and grouping qualifier (wen applicable) Postadress/Postal address: P.O. Box 26, SE751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Pone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se Email: registrator@mpa.se Template version: 20160219