EU PSUR Work Sharing Summary Assessment Report AFLAMIN (aceclofenac) HU/H/PSUR/0030/002 HU

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1 P-RMS EU PSUR Work Sharing Summary Assessment Report AFLAMIN (aceclofenac) HU/H/PSUR/0030/002 HU Invented name of the medicinal product(s) INN (or common name) of the active substance(s) MAHs whose PSURs were included in this work-sharing Pharmacotherapeutic group (ATC Code) Indications authorised in the P-RMS for the product AFLAMIN / AFLAMIN RAPID aceclofenac Almirall / Gedeon Richter / Alprofarma - Laboratorio Temis Farma / Abiogen* (BE, BG, CY, CZ, EE, FR, DE, GR, HU, IT, LV, LT, LU, NL, PL, PT, RO, SK, ES, SE, UK) Accord Healthcare Limited /Intas Pharmaceuticals (IT, LV, PT, SK, UK, FR) Apotex Europe (ES)** Aramis Pharma* (HU) Aristo Pharma Iberia (ES) Extractum Pharma (HU)*, *** Generis Farmaceutica (PT) Germed Farmaceutica (PT) Laboratorios Combix (ES) Laboratorios Pérez Giménez (ES) Mylan / Generics UK* (PT, BE, HU, ES, FR, UK) STADA Arzneimittel (BE, FR, IT, LU, PT, ES) Verisfield UK (CY, UK)** Please note that products may be authorized outside the EU that is not listed above *Authorized in the P-RMS country **P-RMS has been notified of a PSUR being submitted but not in the P-RMS country ***This PSUR did not meet regulatory requirements either concerning submission timelines or format and content M01AB16 (systemic) M02AA25 (topical) Systemic formulations: Acute and chronic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, and other painful conditions of the musculoskeletal system, e.g. scapulo-humeral periarthritis and extra-articular rheumatism. Various painful conditions, e.g. low back pain, odontalgia, primary dysmenorrhoea. Topical formulation: Treatment of local painful and inflammatory

2 Pharmaceutical form(s) and strength(s) conditions of the musculoskeletal system including traumatic injury. It can be used for the antiinflammatory treatment of tendons, ligaments, joints, e.g. sprains, strains and contusions; low back pain, torticollis and periarthritis. 100 mg film-coated tablets 100 mg powder for oral suspension 150 mg powder and solvent for solution for injection 15 mg/1 g cream PSUR Period The period covered by this work sharing assessment was 01/04/ /03/2014. Final Conclusion Aceclofenac is a member of the NSAID class of drugs with both systemic (oral and parenteral) and topical formulations on the EU market. Aceclofenac was first authorised over 20 years ago, and since then, more than 147 million patients have been exposed to the innovator s products. Furthermore, several generics are available all across the EU. In the P-RMS, aceclofenac is indicated for the symptomatic treatment of acute and chronic conditions (including rheumatoid arthritis, extra-articular rheumatism, osteoarthritis, ankylosing spondylitis, scapulohumeral periarthritis, lumbago and odontalgia), to reduce inflammation and pain via inhibition of COX enzymes and thus, reducing the synthesis of prostaglandins. Besides sharing the common mechanism of action of NSAIDs, aceclofenac shows some degree of selectivity towards COX-2 isoform, which is associated with a lower likelihood of certain adverse reactions (e.g. gastrointestinal) enhancing tolerability of the drug as compared to less selective NSAIDs. Efficacy and effectiveness of aceclofenac was established by several studies conducted mainly in the 1990s. No information has been received during the reporting interval of this PSUR that would raise any concerns on efficacy in the approved indications. Safety profile of aceclofenac is well characterized. Safety information identified during the reporting interval is in accordance with previous experience and no new signals have been identified. Nevertheless, cardiovascular safety of traditional (no specificity towards COX-2) NSAIDs has been challenged in recent years, as evidence is accumulating in scientific literature pointing towards an increased risk of arterial thrombotic events, similarly to the risk of specific COX-2 inhibitors (coxibs). This increased risk was confirmed with diclofenac last year, leading to strengthened contraindications, warnings and precautions in the product information of systemic diclofenac-containing medicines. Due to structural similarities and metabolism to diclofenac, and based on a limited number of epidemiological studies, similar amendments are justified in the product information of systemic aceclofenac-containing medicinal products. Almirall, innovator of aceclofenac agreed with PRAC in September 2013 to update the product information, and a variation has already been submitted by the innovator to introduce the changes required. PRAC has reached a conclusion on the specific wording concerning aceclofenac in June 2014 and released its recommendation after the compilation of this PSUR. PRAC also clarified that outcome of this variation procedure is applicable to all systemic products containing aceclofenac. 2

3 Further to arterial thromboembolic events, some signals identified before the current PSUR reporting period will remain under close monitoring and will be analysed in the next PSUR to strengthen or refute causal association. Currently, MAHs of generic aceclofenac are obliged to submit PSURs. Nevertheless, these generic PSURs contained very limited data as compared to the information presented in the innovator s report and did not present any added value during the analysis of safety and efficacy data. Therefore, the P-RMS considers that lifting the obligation to submit PSURs for generic aceclofenac is justified. In the light of the information provided in the reviewed PSUR, the P-RMS considers there were no new major findings affecting the overall safety profile of aceclofenac and the benefit-risk profile of the medicinal products containing aceclofenac remains favourable. Recommendations: Amendments to the Product Information During the assessment of the information in the PSUR the following issue was considered: Product information of systemic aceclofenac-containing medicinal products should be amended to reflect the outcome of the EU referral on the cardiovascular safety of diclofenaccontaining medicinal products (EMEA/H/A-31/1344). Adapting the wording to aceclofenac has already been discussed and agreed during a different procedure upon the request of Spain and a PRAC recommendation has been issued in June This is applicable to all systemic formulations of aceclofenac-containing products. All MAHs concerned are requested to update their product information to be in line with the PRAC recommendation. SmPC wording: [The wordings below should be inserted in the relevant sections] 4.2. Posology and method of administration The following paragraph is inserted if missing Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4 Special warnings and precautions for use) Contraindications Patients with established congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease Special warnings and special precautions for use 3

4 Cardiovascular and cerebrovascular: Patients with congestive heart failure ( NYHA-I) and patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should only be treated with aceclofenac after careful consideration. As the cardiovascular risks of aceclofenac may increase with dose and duration of exposure, the shortest duration possible and the lowest effective daily dose should be used. The patient's need for symptomatic relief and response to therapy should be re-evaluated periodically. Aceclofenac should also be administered with caution and under close medical surveillance to patients with a history of cerebrovascular bleeding 4.8. Undesirable effects Aceclofenac is both structurally related and metabolised to diclofenac for which a greater amount of clinical and epidemiological data consistently point towards an increased risk of general arterial thrombotic events (myocardial infarction or stroke, particularly at high doses and in long treatment). Epidemiological data has also found an increased risk of acute coronary syndrome and myocardial infarction associated with the use of aceclofenac, (see section 4.3 and 4.4 for Contraindications and Special warnings and special precautions for use). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. Leaflet wording [The wordings below should be inserted in the relevant sections] 2. What you need to know before you take <aceclofenac containing medicinal product> Do not use aceclofenac - if you have established heart disease and /or cerebrovascular disease e.g. if you have had a heart attack, stroke, mini-stroke (TIA) or blockages to blood vessels to the heart or brain or an operation to clear or bypass blockages - if you have or have had problems with your blood circulation (peripheral arterial disease) 4

5 Warnings and precautions Talk to your doctor before taking <aceclofenac containing medical product> -If you smoke -If you have diabetes -If you have angina, blood clots, high blood pressure, raised cholesterol or raised triglycerides Medicines such as [product] may be associated with an increased risk of heart attack ("myocardial infarction"). Side effects may be minimised by using the lowest effective dose for the shortest duration necessary. Do not exceed the recommended dose or duration of treatment. 4. Possible side effects If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. Amendment to the PSUR submission obligation for generics: Based on the limited information presented in generic PSURs, and the lack of any added value, the P-RMS recommends lifting the obligation of MAHs of generic aceclofenac to submit PSURs in order to rationalise workload. Agreed topics for close monitoring and review in the next PSUR: The following adverse events should be closely monitored and analysed in the next PSUR by the innovator MAH (Almirall): Arterial thromboembolic reactions including myocardial infarction and stroke Aggravation or flare-up of diverticular disease and diverticulosis 5

6 Serious skin disorders not addressed in the reference safety information/product information, e.g. DRESS syndrome Photosensitivity reactions with the systemic formulation Signal analysis should be supported by clear scientific arguments, and include all available data the MAH is in possession of. 6