Table 3. Exposures to nintedanib in oral repeat dose toxicity and carcinogenicity studies. Species Study duration time of measurement Dose Cmax ng/mL h ng∙h/mL Exposure ratio# IPF indication Exposure ratio# NSCLC indication Based on Cmax Based on AUC Based on Cmax Based on AUC 13 weeks (Day 87) 10 56.95 228 1.8 0.63 1.3 0.42 30 251.5 1315 7.9 3.6 5.8 2.4 100 1025 4735 32 13 24 8.8 (week 26) 5 18.75 40.15 0.59 0.11 0.43 0.07 15 82.2 340.5 2.6 0.94 1.9 0.63 30 261.5 1335 8.2 3.7 6.1 2.5 Rat 4 weeks (Day 28) 3 7.02 10.53 0.2 0.03 0.2 0.02 20 52.25 134 1.6 0.4 1.2 0.3 100 313 1545 9.8 4.3 7.3 2.9 13 weeks (week 13) 3 2.14 5.35 0.1 0.01 0.1 0.01 20 62.6 216.5 2.0 0.6 1.5 0.4 100 246.5 1640 7.7 4.5 5.7 3.0 13 (Day 87) 5 5.32 24.4 0.2 0.1 0.1 0.1 20 31 179 1.0 0.5 0.7 0.3 60 39.65 374 1.2 1.0 0.9 0.7 26 (Day 164-179) 5 7.41 22.8 0.2 0.1 0.2 0.04 20 59.75 250 1.9 0.7 1.4 0.5 80 170.5 1135 5.3 3.1 4.0 2.1 (week 52) 2.5 0.8935 1.66 0.03 0.005 0.02 0.003 5 4.935 25.85 0.15 0.07 0.11 0.05 10 9.83 82.95 0.31 0.23 0.23 0.15
and 200 mg BID (NSCLC) and estimated AUC and Cmax values obtained from the Summary of Clinical Pharmacology Studies, where AUC0-12 was 1.82 ng∙h/mL/mg and Cmax was 0.280 ng/mL/mg in IPF patients and AUC0-12 was 2.03 ng∙h/mL/mg and Cmax was 0.282 ng/mL/mg in NSCLC patients; bold and underlined dose was NOAEL; NA = not applicable. 5. Exposures to BIBF 1202 glucuronide in oral repeat dose toxicity and carcinogenicity studies. Species duration time of Dose Cmax ng/mL h ng∙h/mL Exposure ratio# IPF indication Exposure ratio# NSCLC indication on on AUC on on AUC Mouse 13 weeks (Day 87) 10 63.3 197.5 0.28 0.04 0.21 0.03 30 228.5 968.5 1.0 0.22 0.75 0.16 100 1011 5050 4.4 1.2 3.3 0.86 (week 26) 5 16.5 42.7 0.07 0.01 0.05 0.01 15 78.6 399.5 0.34 0.09 0.26 0.07 30 213.5 1291 0.94 0.29 0.70 0.22 Rat 13 weeks (Day 87) 5 780.5 2065 3.4 0.47 2.6 0.35 20 2425 8150 11 1.9 8.0 1.4 60 6865 30000 30 6.8 23 5.1 26 weeks (Day 5 ND ND - - - - 20 ND ND - - - - 80 ND ND - - - - (week 52) 2.5 295.5 1149 1.3 0.26 0.97 0.20 5 667 2985 2.9 0.68 2.2 0.51 10 1245 5565 5.5 1.3 4.1 0.95 Monkey 52 (Day 363) 10 ND ND - - - - 20 ND ND - - - - ≥ 30 ND ND - - - - IPFa 150 mg BID 228 4410 1 1 NA NA Trial
reactions are presented together for the two products. 9. Liver enzyme elevation and hyper bilirubinaemia is an identified risk for both Vargatef and Ofev. The product label approved by the US FDA for Ofev contains the following detailed instruction on liver function monitoring: ‘Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with Ofev, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations.’ In comparison, the proposed Australian PI provides a more general advice on the frequency of monitoring as follows: ‘Hepatic transaminase and bilirubin levels should be investigated before the initiation of treatment with Ofev/Vargatef and periodically thereafter (for example at each patient visit) or as clinically indicated.’ It is recommended that the Delegate considers this instruction in the context of improvement of the safety. The recommendations for liver function monitoring in the proposed Australian PI are identical to the text approved by the EMA for Ofev (nintedanib in IPF). Hepatic transaminase and bilirubin levels should be investigated before the initiation of treatment with nintedanib, as a baseline reference. The sponsor proposes that start of treatment, liver enzymes and bilirubin should be measured periodically, for example at each patient visit, which could be at the patient’s IPF specialist or family physician, or as clinically indicated. The sponsor anticipates that patients will be followed up by their physician more frequently during the first weeks/months after treatment with nintedanib, according to routine practice following initiation of a new treatment. As the risk of liver enzyme elevations is higher in these first months, the sponsor considers the proposed text in the ASA to be appropriate. Compared to the more detailed recommendation requested by the FDA, the proposed flexible monitoring recommendations in the Australian PI allow the prescribing physicians to provide personalised liver monitoring frequency according to the patient’s medical history, condition, changes in concomitant therapy and so on. The evaluator has noted that the sponsor has updated the Australian PI to align with the relevant parts of the EU Summary of Product Characteristics (SmPC). In regard to the routine risk minimisation, the updated PI is considered acceptable.