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
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
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