of the AEs associated with their use and also of those associated with selexipag, particularly headache, diarrhoea and nausea. Despite multifactorial reasons for patients treated with none, one or two PAH-specific medications prior to entry into GRIPHON, a trend for a more severe baseline disease state in patients with combination therapy compared to treatment-naïve patients is evident. The treatment effect of selexipag in the primary endpoint was consistent across categories of background treatment. In line with published data in PAH patients, the treatment effect on exercise capacity was larger in treatment-naïve patients compared to those pre-treated. The AE safety profile of each sub-group appears to be driven largely by the individual contributions of the respective PAH-specific medications. The use of selexipag on top of existing PAH background therapy targeting endothelin and nitric oxide pathways, as well as in monotherapy, is in line with current PAH treatment guidelines. The mentioned references are provided in updated Module 5.4 Literature References. Given the limited The sponsor will provide further evidence could be The evaluator has long-term safety information provided by clinical noted that two through routine pharmacovigilance trials for this first in planned (PV) monitoring and submission of class product, the safety PBRERs in accordance with the ICH sponsor should study (PASS) studies guideline E2C (R2). In addition, consider the need to have been included further long-term safety data will further characterise the in the updated emerge from the GRIPHON safety profile through One is the study and NS-304/-03 studies. A CSR additional referred by the will be provided once the studies pharmacovigilance sponsor and the other are completed. activities. is to monitor the As an additional PV activity, occurrence of the Actelion is in discussion with the important potential Committee for Medicinal Products risk - medication error, for Human Use (CHMP) regarding and to measure the setting up a long-term, multicenter, effectiveness of the prospective, real-world, additional risk (observational) minimisation activities. Uptravi (selexipag) It is noted that neither safety study. studies are referred in
of the AEs associated with their use and also of those associated with selexipag, particularly headache, diarrhoea and nausea. Despite multifactorial reasons for patients treated with none, one or two PAH-specific medications prior to entry into GRIPHON, a trend for a more severe baseline disease state in patients with combination therapy compared to treatment-naïve patients is evident. The treatment effect of selexipag in the primary endpoint was consistent across categories of background treatment. In line with published data in PAH patients, the treatment effect on exercise capacity was larger in treatment-naïve patients compared to those pre-treated. The AE safety profile of each sub-group appears to be driven largely by the individual contributions of the respective PAH-specific medications. The use of selexipag on top of existing PAH background therapy targeting endothelin and nitric oxide pathways, as well as in monotherapy, is in line with current PAH treatment guidelines. The mentioned references are provided in updated Module 5.4 Literature References. Given the limited evidence could be provided by clinical trials for this first in class product, the sponsor should consider the need to further characterise the safety profile through additional pharmacovigilance activities. The sponsor will provide further long-term safety information through routine pharmacovigilance (PV) monitoring and submission of PBRERs in accordance with the ICH guideline E2C (R2). In addition, further long-term safety data will emerge from the GRIPHON and NS-304/-03 studies. A CSR will be provided once the studies are completed. As an additional PV activity, Actelion is in discussion with the Committee for Medicinal Products for Human Use (CHMP) regarding setting up a long-term, multicenter, prospective, real-world, (observational) Uptravi (selexipag) safety study. The evaluator has noted that two planned safety study (PASS) studies have been included in the updated One is the study referred by the sponsor and the other is to monitor the occurrence of the important potential risk - medication error, and to measure the effectiveness of the additional risk minimisation activities. It is noted that neither studies are referred in
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