risk for both Dupuytren’s and Peyronie’s indications. potential risk for Peyronie’s disease in 2 circumstances: use to treat a ventral deformity of the penis and use to treat an isolated hourglass deformity of the penis. In both circumstances, use of Xiaflex could result in injury to the urethra because of the location of the plaque, and, thus, lead to permanent damage. However, off-label use in Dupuytren’s contracture was not considered to be an important potential risk in either Version 10 or Version 11 of the RMP. During the clinical program for Dupuytren’s contracture, the only restriction for the treatment of Dupuytren’s was in the thumb. This restriction was not for safety reasons but because of the difficulty in assessing efficacy in a joint that moves in multiple planes. The prescribing information in the United States and EU does not prohibit use in the thumb and thus, this is not an off-label use. A search was performed of the global safety database to determine if any off-label use has occurred with Xiaflex for Dupuytren’s contracture. No cases have been received representing off-label use for Dupuytren’s contracture. Based on this information, the MAH believes there is no basis to include off-label use as an important potential risk for the indication of Dupuytren’s contracture as no such circumstance has been identified or reported. EU RMP Version 11 is provided in updated Module 1.8.1. Pharmacovigilance Systems. irrespective of indication. However, taking into account the risk minimisation measures in place for the Dupuytren’s indication and proposed for the Peyronie’s indication the sponsor’s response to this recommendation is acceptable at this time. According to milestones stated in the pharmacovigilance plan, Study AUX-CC-806 has been completed. The sponsor should provide an update to Study AUX-CC-806 has been completed and a copy of the full CSR is provided. The efficacy results of this study demonstrate the therapeutic effectiveness of Xiaflex in the This is acceptable.
Details of the certification process are included in the amended ASA, Module 1.8.2 Risk Management Plan for Australia. The sponsor should provide details as to which groups of medical practitioners will be able to access the Peyronie’s training. Certification will be restricted to urologists and sexual health physicians. This is acceptable from an RMP perspective. The Australian PI should contain the following clinically relevant statement appears in the EU Summary of Product Characteristics (SmPC): Patients with penile curvature >90° were not included in the clinical studies. Treatment in this group can therefore not be recommended. The sponsor acknowledges the recommendations of the evaluator and has amended the AU PI accordingly. The new text will appear in the Clinical trials section of the AU PI. The AU PI has been amended so that the clinical section contains this additional statement Patients with penile curvature >90° were not included in the clinical studies. Treatment in this group can therefore not be recommended The amended AU PI was provided. This is acceptable from an RMP perspective. PI amendments are subject to approval by the Delegate. It is noted that the EU SmPC contains a detailed description of the penile modelling procedure however the proposed PI does not. The Delegate should consider inclusion of this information in the PI if appropriate. Each pack of Xiaflex will contain two inserts: one for the treating physician and one (CMI) for the patient. The physician's insert will contain the PI and an integrated "Physician's Guide". The Physician's Guide will contain detailed information regarding the preparation and reconstitution of Xiaflex, administration of the injection as well as information on the penile modelling procedure. The CMI insert will contain detailed information on the penile modelling procedure as well as other text normally required in the CMI. The Physician leaflet was provided. The sponsor’s approach is acceptable from an RMP perspective. The EU SmPC contains the following clinically relevant The sponsor acknowledges the recommendations of the This is acceptable from an RMP perspective.
the EU SmPC is more restrictive. ASA guidance can be found on the TGA website. The EU RMP version 11 and the amended ASA were provided. Summary of recommendations It is considered that the sponsor’s response to the TGA’s request for further information has adequately addressed the issues identified in the RMP evaluation report Additional recommendations are summarised Outstanding issues Issues in relation to the RMP The clinical evaluator has recommended that ‘Use in the elderly’ be as an item of missing information to the RMP and/or the ASA. The sponsor should add this item of missing information to the RMP and/or the ASA prior to finalisation unless a compelling justification can be provided for its omission. It is considered that routine risk minimisation and pharmacovigilance would be acceptable for this additional item of missing information. The evaluator has no objection to the educational materials. Once finalised, these should be provided to the TGA. Advice from the Advisory Committee on the Safety of Medicines (ACSOM) ACSOM advice was not sought for this submission. Key changes to the updated RMP EU-RMP version 10.0 (dated 9 May 2014, DLP 16 December 2013) and Australian Specific Annex version 4.0 (dated 28 January 2015) has been superseded by EU-RMP version 11.0 (dated 29 April 2015, DLP 27 February 2015) and Australian Specific Annex version 5.0 (dated 8 September 2015) and the key changes are summarised below in Table 8. 8: Summary of key changes to the EU-RMP Summary of key changes noted between EU RMP v10/ASA v4 and EU RMP v11/ASA v5 Safety specification New potential ‘Immune mediated reactions’, ‘Skin Lesions’, ‘Injury of the Urethra’, ‘Off label use in patients with ventral curvature deformity’, ‘Off label use in patients with isolated hourglass deformity’. activities Pharmacovigilance plan for new potential risks added (NB these safety concerns appear to have been incorporated into existing pharmacovigilance activities – a targeted questionnaire is also proposed for ‘Immune mediated reactions’). Risk minimisation activities Risk minimisation activities are now proposed for the new potential risks A non-interventional post-authorisation safety study is now proposed to evaluate the effectiveness of the implemented additional risk minimisation measures in the EU.