resulted in decreased for tolerability of exposure to nintedanib is thus nintedanib. not considered to convey a Management of safety risk. side effects may require The effect of the concomitant interruption, dose use of P-gp inhibitors and reduction, or inducers with nintedanib in discontinuation of the clinical setting in patients therapy with with IPF and NSCLC was OFEV (see Dosage investigated by the Phase and II/III PopPK analysis and in Administration). the PK analyses of Trials 1199.32 and 1199.34. No Potent P-gp significant influence of P-gp inducers (for inducers or P-gp inhibitors on example nintedanib exposure was rifampicin, identified in any of these carbamazepine, analyses. phenytoin, and St. John’s Wort) may Analyses based on data from decrease exposure the clinical setting as used for to nintedanib. the PopPK analysis and the Selection of an PK investigations of Phase III alternate data may better reflect concomitant clinical routine compared to a medication with dedicated Phase I DDI study, no or minimal even if there are certain induction limitations as the dose taken, potential should the route of administration, be considered.’ and time of intake for P-gp inducers and Pgp inhibitors Therefore, the relative to nintedanib were evaluator not recorded. Also, the considers that number of patients using P-gp the potential inducers or strong P-gp safety risk inhibitors, that is model related to drug inhibitors of P-gp as specified interaction with in regulatory DDI guidelines, P-gp was low: less than 8% of PK observations were associated has been with concomitant intake of a adequately P-gp inducer and P-gp addressed. inhibitor in the PopPK analysis, respectively. on the totality of the available data, the sponsor suggests that the current description in the DDI section of the proposed label provides appropriate guidance for the prescriber. Management of the side effects potentially resulting from increased exposure to
resulted in decreased exposure to nintedanib is thus not considered to convey a safety risk. The effect of the concomitant use of P-gp inhibitors and inducers with nintedanib in the clinical setting in patients with IPF and NSCLC was investigated by the Phase II/III PopPK analysis and in the PK analyses of Trials 1199.32 and 1199.34. No significant influence of P-gp inducers or P-gp inhibitors on nintedanib exposure was identified in any of these analyses. Analyses based on data from the clinical setting as used for the PopPK analysis and the PK investigations of Phase III data may better reflect clinical routine compared to a dedicated Phase I DDI study, even if there are certain limitations as the dose taken, the route of administration, and time of intake for P-gp inducers and Pgp inhibitors relative to nintedanib were not recorded. Also, the number of patients using P-gp inducers or strong P-gp inhibitors, that is model inhibitors of P-gp as specified in regulatory DDI guidelines, was low: less than 8% of PK observations were associated with concomitant intake of a P-gp inducer and P-gp inhibitor in the PopPK analysis, respectively. on the totality of the available data, the sponsor suggests that the current description in the DDI section of the proposed label provides appropriate guidance for the prescriber. Management of the side effects potentially resulting from increased exposure to for tolerability of nintedanib. Management of side effects may require interruption, dose reduction, or discontinuation of therapy with OFEV (see Dosage and Administration). Potent P-gp inducers (for example rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may decrease exposure to nintedanib. Selection of an alternate concomitant medication with no or minimal induction potential should be considered.’ Therefore, the evaluator considers that the potential safety risk related to drug interaction with P-gp has been adequately addressed.