Second evaluation of clinical data submitted in response to questions For details of the Clinical Questions and the sponsor’s responses and the evaluation of these responses please see Attachment 2. Second round benefit-risk assessment The extra material provided by the sponsor in their response does not materially alter any of the conclusions listed in the First Round CER. The evaluator concedes that the reduced abuse potential of Targin via the intravenous and intranasal routes is of value but remains of the opinion that this benefit must be balanced against the residual risk of abuse via the oral chewed route in subjects not on methadone. The evaluator remains concerned that exposure to the highest proposed dose of Targin has been very limited, falling well short of the recommended exposure required for adequate demonstration of efficacy and safety. Second round recommendation regarding authorisation Recommendation regarding RLS The sponsor’s application to register Targin for the treatment of RLS that has not responded adequately to dopaminergic therapy should be approved. Recommendation regarding higher maximum dose The sponsor’s application to register Targin at the proposed maximum dose of 80/40 mg twice daily should be rejected (for the reasons listed above). Recommendation regarding proposed discussion of abuse potential in PI The sponsor’s application to modify the PI to include discussion of abuse potential should be approved, but the PI should be further modified. V. Pharmacovigilance findings Risk management plan The sponsor submitted a Risk Management Plan (EU-RMP Version 5.0 12 September 2013, Data Lock Point (DLP) 12 April 2013) and Australian Specific Annex Version 5.0 (dated June 2015); EU-RMP Version 6.0 (dated 23 September 2015, DLP 31 July 2015) with Australian Specific Annex Version 6.0 (dated January 2016)) which was reviewed by the RMP evaluator. Safety specification The sponsor provided a summary of ongoing safety concerns are shown at Table 14. Table 14: Summary of ongoing safety concerns Summary Ongoing Safety Concerns Constipation
Table 16: Key changes between EU-RMP versions 5.0 and 6.0 Summary of key changes between EU RMP Version 5.0 and EU RMP Version 6.0 Safety specification ‘Overdose’ and ‘Medication have been added as Important Identified Risks ‘Physical dependence and drug withdrawal syndrome’ has been changed to ‘Drug dependence and drug withdrawal syndrome’ as an Important Identified Risk ‘Accidental overdose’ has been removed as an Important Potential Risk ‘Psychological dependence’ has been removed as an Important Potential Risk ‘Serious hepatic events’ has been changed to ‘Hepatic Disorders’ as an Important Potential Risk attack/reaction’ has been added as an Important Potential Risk ‘Aphasia’ has been as an Important Potential Risk ‘Paediatric Use’ as Missing Information has been changed to ‘Use in paediatric patients < 18 ‘Use in patients with hepatic impairment’ and ‘Use in patients with renal impairment’ have been added as Missing Information ‘Off-label use in RLS’ has been changed to ‘Off-label use’ as Missing Information Pharmacovigilance activities Epidemiological OXN9514 has been added as additional Pharmacovigilance for the safety concerns of ‘Drug dependence and drug withdrawal syndrome’ and ‘Drug abuse, misuse and diversion’ Risk minimisation activities Only routine risk minimisation is now proposed for all safety concerns (reference to educational materials has been removed in EU RMP Version 6.0). ASA The ASA has not been updated to reflect the Safety Specification in Version 6.0 of the EU RMP; it reflects the safety concerns of EU RMP Version 5.0, but with removal of the educational materials as additional risk minimisation. The ASA (as Version 6.0) should be updated to reflect the safety concerns identified in Version 6.0 of the EU RMP. Suggested wording for conditions of registration RMP The RMP wording for conditions of registration cannot be provided at this time. Suggested wording cannot be provided until the outstanding RMP issues detailed in this report are satisfactorily addressed. VI. Overall conclusion and risk/benefit assessment The submission was summarised in the following Delegate’s overview and recommendations: