NP29042 The TRAEs reported in this study are summarised in Table 36. Table 36: TRAEs in Study NP29042 TRAEs: causality probable remotely condition possible alectinib 4 4 (16.7%) decreased myalgia gingival alone appetite bleeding, headache (N=24) rifampin 26 16 chromaturia abdominal contact alone (66.7%) (x14), dermatitis abnormality, , (N=24) urine odour abnormal, dyspepsia, faeces discoloured (x2), infrequent bowel movements (x2), nausea, headache (x2) alectinib + 3 3 (12.5%) abdominal dyspepsia dermatitis rifampin pain, contact chromaturia (N=46) Comment: It is noted that there are 14 reports of chromaturia in Period 2 with rifampin alone dosing, yet there is only one report of chromaturia in Period 3 when rifampin and alectinib were given concurrently. This can be explained by the fixed-sequence nature of the study, given that rifampin dosing was continuous daily throughout Period 2 and into the directly consecutive Period 3. Deaths and trial serious adverse events (SAEs) Integrated safety analyses An overview of deaths and cause of death for the pivotal trials up until the middle of 2015 is provided in Table 37. Of the seven deaths that were not due to disease progression, all but two are described above. The two previously undescribed cases are Endocarditis (subject [information redacted] of Study NP28673) Endocarditis occurred day 380 A [information redacted]-year-old White male (enrolled in Italy) developed progressive disease on Study Day 345, and was changed to 3’ of the study ‘Part – that is, post-progression treatment with alectinib. On Day 380, he was hospitalised with dyspnoea, and an echocardiogram showed endocarditis. He was treated with vancomycin and meropenem but died of worsening endocarditis on Study Day 387. This event was considered not related to the study drug. (subject [information redacted] of Study NP28671) A death with unknown cause was reported.
NP29042 The TRAEs reported in this study are summarised in Table 36. Table 36: TRAEs in Study NP29042 condition TRAEs: probable causality remotely possible alectinib alone (N=24) 4 4 (16.7%) decreased appetite myalgia gingival bleeding, headache rifampin alone (N=24) 26 16 (66.7%) chromaturia (x14), abnormality, urine odour abnormal, dyspepsia, faeces discoloured (x2), infrequent bowel movements (x2), nausea, headache (x2) abdominal contact dermatitis alectinib + rifampin (N=46) 3 3 (12.5%) abdominal pain, chromaturia dyspepsia dermatitis contact Comment: It is noted that there are 14 reports of chromaturia in Period 2 with rifampin alone dosing, yet there is only one report of chromaturia in Period 3 when rifampin and alectinib were given concurrently. This can be explained by the fixed-sequence nature of the study, given that rifampin dosing was continuous daily throughout Period 2 and into the directly consecutive Period 3. Deaths and serious adverse events (SAEs) Integrated safety analyses An overview of deaths and cause of death for the pivotal trials up until the middle of 2015 is provided in Table 37. Of the seven deaths that were not due to disease progression, all but two are described above. The two previously undescribed cases are Endocarditis (subject [information redacted] of Study NP28673) Endocarditis occurred day 380 A [information redacted]-year-old White male (enrolled in Italy) developed progressive disease on Study Day 345, and was changed to ‘Part 3’ of the study – that is, post-progression treatment with alectinib. On Day 380, he was hospitalised with dyspnoea, and an echocardiogram showed endocarditis. He was treated with vancomycin and meropenem but died of worsening endocarditis on Study Day 387. This event was considered not related to the study drug. (subject [information redacted] of Study NP28671) A death with unknown cause was reported. , trial