56 Early experience of the Orkambi “Managed Access Programme” in a regional adult UK CF centre

Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review

“…In the observational studies, the number of subjects included ranged from 4 to 845 (median: 28). Fourteen (26%) of the observational studies focused on patients with severe airflow obstruction, defined as ppFEV 1 < 40%; in 11 of these studies, patients accessed the CFTR modulator via a compassionate access program (also referred to as a “managed access”, “early access’, “expanded access”, or “named patient” program) through the manufacturer [ 25 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. Twenty (65%) of the full manuscripts were deemed to have safety as a primary focus or outcome [ 27 , 28 , 29 , 30 , 32 , 33 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ].…”

“…The majority of AEs reported with LUM/IVA were respiratory-related. Chest tightness, dyspnea, increased sputum, and declines in ppFEV 1 were among the most common respiratory AEs and tended to occur within the first few days after initiation, even as quickly as 3–4 h after the first dose [ 25 , 26 , 27 , 31 , 32 , 33 , 34 , 35 , 37 , 38 , 41 , 42 , 43 , 44 , 45 , 60 , 61 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 83 , 84 , 85 , 90 ]. Bronchodilators were beneficial in mitigating symptoms of chest tightness, wheeze, and increased work of breathing in some individuals [ 31 , 41 , 66 , 67 , 75 ].…”

“…In one case report, halving the LUM/IVA dose mitigated severe chest tightness, dyspnea, and exertional hypoxemia that onset after initiation, but therapy was ultimately discontinued with rapid recovery of symptoms and ppFEV 1 thereafter [ 90 ]. A cohort study also reported resolution of respiratory AE upon LUM/IVA discontinuation [ 35 ]. In observational studies that described retrials after LUM/IVA was discontinued, there were mixed outcomes among patients.…”

“…A number of factors and patient characteristics were explored as potential risk factors for respiratory AE and/or discontinuation due to AE with LUM/IVA. Having a lower baseline ppFEV 1 was generally associated with greater risk of respiratory AE or discontinuation [ 26 , 42 , 73 , 75 , 77 ], but differences were not always statistically significant [ 33 , 35 , 44 , 61 ], and one study found the contrary [ 43 ]. One study, using multivariable logistic regression, found for every 10% decrease in baseline ppFEV 1 , there was a greater likelihood of LUM/IVA discontinuation overall and due to respiratory AE—odds ratio (OR) 1.13 (95%CI, 1.02–1.25; p = 0.02) and OR 1.32 (95%CI, 1.14–1.51; p = 0.0001), respectively [ 42 ].…”

“…Rash and hypersensitivity reactions were notable with LUM/IVA. In several observational studies reporting rash, LUM/IVA was seemingly continued without intervention, but prompted discontinuation in a small number of patients [ 26 , 33 , 35 , 42 , 44 , 73 , 76 , 78 ]. More serious reactions in the observational studies were rash with facial swelling, allergic reaction with chest tightness, and suspected Stevens–Johnson syndrome (SJS), reported in one individual each [ 61 , 75 ].…”