Final SmPC and PL wording agreed by PhVWP in June 2012

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1 Association of oxcarbazepine (Trileptal) with risk of hypersensitivity adverse drug reactions potentially associated with the alleles HLA-A*3101 HLA- B*1502 Final SmPC and PL wording agreed by PhVWP in June 2012 Doc.Ref.: CMDh/PhVWP/054/2012 July 2012 SUMMARY OF PRODUCT CHARACTERISTICS (Additions are in bold and deletions are in strikethrough) HLA-B*1502 allele in Han Chinese, Thai and other Asian populations HLA-B*1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as Stevens- Johnson syndrome (SJS) when treated with carbamazepine. The chemical structure of oxcarbazepine is similar to that of carbamazepine, and it is possible that patients who are positive for HLA B*1502 may also be at risk for SJS after treatment with oxcarbazepine. There are some data that suggest that such an association exists also for oxcarbazepine. The prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine or screening for a chemically-related active substance should be considered. If patients of these origins are tested positive for HLA B*1502 allele, the use of [drug] may be considered if the benefits are thought to exceed risks. Because of the prevalence of this allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be considered. The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (< 1%). HLA-A*3101 allele European descent and Japanese populations There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people of European descent and the Japanese. The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA- A*3101 allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. oxcarbazepine (Trileptal) with risk of hypersensitivity adverse drug reactions July 2012 Page 1/2

2 There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine or chemically-related compounds treatment. If patients of European descent or Japanese origin are known to be positive for HLA- A*3101 allele, the use of carbamazepine or chemically-related compounds may be considered if the benefits are thought to exceed risks. PACKAGE LEAFLET Package Leaflet Information The risk of serious skin reactions in patients of Han Chinese or Thai origin associated with carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these patients. Your doctor should be able to advise if a blood test is necessary before taking oxcarbazepine. oxcarbazepine (Trileptal) with risk of hypersensitivity adverse drug reactions July 2012 Page 2/2

3 Dutch translation SAMENVATTING VAN DE PRODUCTKENMERKEN Rubriek 4.4 Bijzondere waarschuwingen en voorzorgen bij gebruik HLA-B*1502-allel bij Han-Chinese, Thaise en andere Aziatische bevolkingsgroepen HLA-B*1502 in individuen van Han-Chinese of Thaise afkomst blijkt sterk geassocieerd te zijn met het risico op het ontwikkelen van de ernstige huidreacties, bekend als het Stevens-Johnson syndroom (SJS), wanneer behandeld met carbamazepine. De chemische structuur van oxcarbazepine is vergelijkbaar met die van carbamazepine en het is daardoor mogelijk dat patiënten die positief zijn voor HLA-B*1502 ook risico lopen op SJS bij behandeling met oxcarbazepine. Er zijn enkele gegevens die erop duiden dat een dergelijk verband ook voor oxcarbazepine bestaat. De prevalentie van HLA-B*1502-dragers onder Han-Chinezen en Thai is ongeveer 10%. Voordat behandeling met carbamazepine of een chemische verwant werkzaam bestanddeel wordt gestart, dienen deze mensen waar mogelijk te worden gescreend op dit allel Als patiënten van deze afkomst positief getest zijn op het HLA-B*1502-allel dan kan gebruik van <productnaam> worden overwogen als de voordelen naar verwachting groter zijn dan de risico's. Vanwege de prevalentie van dit allel bij andere Aziatische bevolkingsgroepen (bijvoorbeeld meer dan 15% op de Filippijnen en in Maleisië) kan worden overwogen patiënten uit risicopopulaties genetisch te testen op aanwezigheid van HLA-B*1502. De prevalentie van het HLA-B*1502-allel is verwaarloosbaar bij bijvoorbeeld mensen van Europese afkomst, Afrikaanse populaties, de onderzochte Latijns-Amerikaanse populaties, en bij Japanners en Koreanen (<1%). HLA-A*3101-allel Europese afkomst en Japanse populaties Er zijn enkele gegevens die erop duiden dat HLA-A*3101 in Europese en Japanse populaties mogelijk geassocieerd is met een verhoogd risico op door carbamazepine geïnduceerde cutane bijwerkingen, waaronder SJS, TEN, geneesmiddel geïnduceerde huiduitslag met eosinofilie (DRESS) of minder ernstige acute gegeneraliseerde exanthemateuze pustulose (AGEP) en maculopapulaire huiduitslag. De frequentie van het HLA-A*3101-allel loopt in verschillende etnische bevolkingsgroepen sterk uiteen. Het HLA-A*3101-allel heeft in Europese populaties een prevalentie van 2-5% en in de Japanse populatie een prevalentie van ongeveer 10%. Bij aanwezigheid van het HLA-A*3101-allel neemt het risico op carbamazepine-geïnduceerde huidreacties (meestal minder ernstig) toe van 5% in de algemene bevolking tot 26,0% bij individuen van Europese afkomst, terwijl bij afwezigheid van dit allel het risico afneemt van 5% tot 3,8%. Er zijn onvoldoende gegevens om een aanbeveling te onderbouwen voor screening op HLA- A*3101 voordat met een behandeling met carbamazepine of chemisch verwante verbindingen wordt begonnen. Als van een patiënt van Europese of Japanse afkomst bekend is dat hij/zij positief is voor het HLA-A*3010-allel dan kan gebruik van carbamazepine of chemisch verwante verbindingen worden overwogen als de voordelen naar verwachting groter zijn dan de risico's.

4 BIJSLUITER Rubriek 2: Wanneer mag u dit middel niet gebruiken of moet u er extra voorzichtig mee zijn? Het risico op ernstige huidreacties in verband met carbamazepine of chemisch verwante stoffen kan bij patiënten van Han-Chinese of Thaise afkomst worden voorspeld aan de hand van bloedonderzoek bij deze patiënten. Uw arts dient u te kunnen adviseren of bloedonderzoek noodzakelijk is voordat u oxcarbazepine gaat gebruiken.

5 Annex 2 Summary Assessment Report of the PhVWP July 2012 Oxcarbazepine Risk of skin reactions potentially associated with HLA-A*3101 and HLA-B*1502 alleles Key message Carbamazepine-induced severe cutaneous adverse reactions (SCAR) in European Caucasians and Japanese patients are associated with a newly identified genetic marker, HLA-A*3101, but routine testing for HLA-A*3101 allele in European Caucasians and Japanese patients is not recommended for carbamazepine or the structurally related oxcarbazepine. If European Caucasians or patients of Japanese descent are known to be positive for HLA-A*3101 allele, the use of oxcarbazepine may be considered if the benefits are thought to exceed the risks. Carbamazepine-induced SCAR are also associated with the HLA-B*1502 allele, and clinical utility of testing for HLA-B*1502 allele in patients of Han Chinese and Thai origin has been proven. Individuals of Han Chinese and Thai populations should, whenever possible, be tested for the HLA-B*1502 allele before starting treatment with the structurally related oxcarbazepine. Testing for the HLA-B*1502 allele in other Asian populations may be considered. Safety concern and reason for current safety review Oxcarbazepine is structurally related to carbamazepine, and during the review of severe cutaneous adverse reactions induced by carbamazepine in association with the HLA-B*1502 and HLA-A*3101 alleles (see Summary Assessment Report 3), the concern arose that oxcarbazepine could have a similar risk or that there could be a risk of cross-reactivity with carbamazepine. Clinical setting Oxcarbazepine is a derivate of carbamazepine and belongs to the class of second generation antiepileptics. It is effective as a short-term combination treatment for patients with drug-resistant partial epilepsy. Cutaneous adverse reactions are adverse reactions affecting the skin. Information on the data assessed The data assessed derived from ongoing or completed clinical trials and from case reports published in the medical literature [1-5]. Further, data collected through spontaneous reporting schemes in Member States were reviewed. Outcome of the assessment With regard to data from spontaneous reporting schemes in Member States, the reporting rates of cutaneous adverse reactions for oxcarbazepine range from rare to very rare between Member States. Based on the cumulative analysis of the safety data from the marketing authorisation holder s clinical trial programme, cutaneous hypersensitivity and other hypersensitivity reactions with delayed onset were reported in only a minority of patients (reporting rates: 0.9% for oxcarbazepine-treated patients and 1.1% for placebo/control patients). PhVWP Monthly report on safety concerns, guidelines and general matters July 2012 EMA/CHMP/PhVWP/438980/2012 Page 21/42

6 There is a limited number of case reports and studies in the medical literature linking oxcarbazepineinduced cutaneous adverse reactions to the HLA-B*1502 allele: 4 patients in study [2], 3 patients in study [3] and 2 individual case reports [4, 5]. There are no publications to date linking oxcarbazepine-induced adverse reactions to the HLA-A*3101 allele. Based on results from a case-control study showing a statistically significant association between the HLA-B*1502 allele and oxcarbazepine-induced cutaneous reactions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [3], as well as cross-reactivity in carbamazepine-sensitised individuals receiving oxcarbazepine, the PhVWP concluded that the demonstrated strong association between the HLA-B*1502 allele and SJS/TEN cannot be excluded for carbamazepine-related substances (iminiostilbene antiepileptics). Therefore, despite that data are limited, the PhVWP recommended that the product information for oxcarbamazepine should include advice similar to that for carbamazepine-containing products. The PhVWP recommended that the summaries of product characteristics (SmPCs) (and accordingly the package leaflets (PLs)) of oxcarbamazepine-containing medicinal products authorised in the EU should be updated to include, in SmPC section 4.4, that: - the HLA-B*1502 allele in individuals of Han Chinese and Thai origin has been shown to be strongly associated with the risk of developing the severe cutaneous reactions known as SJS when treated with carbamazepine; the chemical structure of oxcarbazepine is similar to that of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk for SJS after treatment with oxcarbazepine; and there are some data that suggest that such an association exists also for oxcarbazepine; - the prevalence of HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations; whenever possible, these individuals should be screened for this allele before starting treatment with carbamazepine or a chemically-related active substance; if patients of these origins have tested positive for the HLA-B*1502 allele, the use of oxcarbazepine may be considered if the benefits are thought to exceed risks; - because of the prevalence of the HLA-B*1502 allele in other Asian populations (e.g. above 15% in the Philippines and Malaysia), genetic testing of at risk populations for the presence of HLA-B*1502 may be considered; - the prevalence of the HLA-B*1502 allele is negligible in e.g. persons of European descent, African populations, Hispanic populations sampled and in Japanese and Koreans (< 1%); - there are some data that suggest that the HLA-A*3101 allele is associated with an increased risk of carbamazepine-induced cutaneous adverse reactions including SJS, TEN, drug rash with eosinophilia (DRESS), or less severe acute generalised exanthematous pustulosis (AGEP) and maculopapular rash in people of European descent and the Japanese; - the frequency of the HLA-A*3101 allele varies widely between ethnic populations; the HLA-A*3101 allele has a prevalence of 2-5% in European populations and about 10% in Japanese population; - the presence of HLA-A*3101 allele may increase the risk for carbamazepine-induced cutaneous reactions (mostly less severe) from 5.0% in the general population to 26.0% among subjects of European ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%; - there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting carbamazepine or chemically-related compound treatment; - if patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, the use of carbamazepine or chemically-related compounds may be considered if the benefits are thought to exceed risks. PhVWP Monthly report on safety concerns, guidelines and general matters July 2012 EMA/CHMP/PhVWP/438980/2012 Page 22/42

7 References [1] Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev. 2000; 3: CD [2] Hu FY, Wu XT, An DM, et al. Pilot association study of oxcarbazepine-induced mild cutaneous adverse reactions with HLA-B*1502 allele in Chinese Han population. Seizure. 2011; 20: [3] Hung SI, Chung WH, Liu ZS, et al. Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics. 2010; 11: [4] Chen YC, Chu CY, Hsiao CH. Oxcarbazepine-induced Stevens-Johnson syndrome in a patient with HLA-B*1502 genotype. J Eur Acad Dermatol Venereol. 2009; 23: [5] Shankarkumar U, Shah KN, Ghosh K. HLA B*1502 allele association with oxcarbamazepine-induced skin reactions in epilepsy patient from India [letter]. Epilepsia. 2009; 50: PhVWP Monthly report on safety concerns, guidelines and general matters July 2012 EMA/CHMP/PhVWP/438980/2012 Page 23/42

8 Registratiehouder ( t.a.v. registratieafdeling) Your letter Your reference Utrecht, Case number Case manager Our reference../../ Telephone number Subject Request for change in the product information following the PhVWP/CMDh decision Oxcarbazepine Risk of skin reactions potentially associated with HLA-A*3101 and HLA- B*1502 alleles. Following assessment of the available data assessed by the PhVWP on the association of oxcarbazepine (Trileptal) with the risk of hypersensitivity adverse drug reactions potentially associated with the alleles HLA-A*3101 and HLA-B*1502, all Marketing Authorisation (MA) holders for products with oxcarbazepine as active ingredient are being requested to submit type IB variations (variation number C1.3.a) (or equivalent national procedures see below) for their relevant products to implement the PhVWP/CMD(h) decision. Link to the website with the published decision: You are requested to change the SmPC and Package Leaflet (PL) of <product> < RVG> The agreed texts, together with the translation in Dutch, are attached to this letter. These texts should be included literally in the SmPC and PL. However, you are requested to check the SmPC and PL carefully to make sure that there is no overlap with the current texts. If there is such overlap, you should replace the current text with wording from the agreed texts. With regard to PL wording, further user testing by individual MA holders will not be expected on this occasion. For products registered via an MRP or DCP procedure, the RMS takes responsibility on behalf of the CMSs to request the variation from the MA holder and initiate the procedure. The applications do not require supporting information or expert statements and will be accepted by Member States Competent Authorities without further assessment or amendment. If there is no reason to update your product information via a type IB variation, you are requested to reply to this letter with a statement that the product information does not need to be changed.

9 How to submit this variation in the Netherlands C B G M E B The MEB has pre-assigned you the following case number for this variation: <XXXXX>. You are requested to send your application data package and future correspondence to the case@cbg-meb.nl address. Please mention the following information. Subject field of the o Case number <XXXXX> o Name of the medicinal product and RVG number or Procedure number (if NL=RMS) Message body: o Case number <XXXXX> o Implementation of the PhVWP/CMD(h) decision by request of the MEB. Attachments: o Completed application form o Checked guideline regarding the variation o Product information (SmPC, PL and/or labeling, if applicable) affected with this variation (tracked and clean in a Word format). If the product was registered via MRP/DCP with NL = RMS, you are also asked to include a dispatch list with the submission dates in the CMSs. Please, be informed that you have to submit in such case, both the English texts and the national translations. Timetable for implementation You should submit variations no later than 1 October On behalf of the Medicines Evaluation Board in the Netherlands, Drs. A.H.P. van Gompel This notification has been produced centrally in an automated process and consequently does not bear a signature. Attachments: Annex 1: agreed texts (UK and Dutch versions) Annex 2: Summary assessment report

10 ANNEX 1 I Final SmPC/PIL wording agreed by PhVWP/CMDh June 2012 C B G M E B