French Nationwide Cohort Temporary Utilization Authorization Survey of GranuPAS® in MDR-TB Patients

Background: Para-aminosalicylic acid (PAS) is again needed for the treatment of multidrug and extensively drug-resistant tuberculosis (M/XDR-TB). The study of a new granulated formulation (PAS-GR, ‘GranuPAS®'), which might have fewer adverse events, was made possible by the statutory requirement that data be collected regarding its use in France in multidrug-resistant TB (MDR-TB) patients under a ‘therapeutic utilization' follow-up for safety and efficacy system called ‘Autorisation Temporaire d'Utilisation' (ATU). Methods: In May 2011 an ATU cohort was established to monitor the named patient use of PAS-GR. All patients were included in a follow-up protocol developed by Lucane Pharma and the French Medicines Agency (ANSM) which recorded demographics, dosing characteristics, concomitant medications, adverse events, and outcome. Following EU marketing authorization, the ATU terminated about 3 years after initiation. Results: PAS-GR was used for the treatment of 231 MDR-TB patients. PAS-GR was used at 12 g/day in 114 cases and 8 g/day in 80 cases. PAS-GR-containing combinations resulted in sputum conversion in a median of 94 days (IQR 48-143) in the 55 patients with information after treatment initiation. Adverse effects of PAS-GR-containing combinations were mostly gastrointestinal (GI; 9% of patients experiencing a GI event at any time) and led to interrupt PAS-GR in 6% of cases (2.1% GI). Conclusions: The efficacy of PAS-GR appears equivalent to that of PAS, and its tolerance improved over earlier PAS formulations, thus supporting the use of PAS-GR as part of drug combinations for the treatment of MDR and XDR-TB.