Introduction: Lumacaftor-ivacaftor is indicated for treatment of cystic fibrosis (CF) in patients homozygous for the Phe-508del cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. In clinical trials, treated patients showed improved pulmonary function, reduced pulmonary exacerbations, and other benefits. This article reviews safety of this therapy. Areas covered: Safety findings in ivacaftor, lumacaftor and combined therapy trials, and reported subsequently through post-approval evaluation, were accessed by PubMed and Google searches using key words “VX-770”, “ivacaftor”, “VX-809”, and “lumacaftor”. Transaminitis was seen in ivacaftor and combination trials. Non-congenital cataracts were seen in pre-clinical animal studies and in children taking ivacaftor and combined therapy. Dyspnea occurs in some patients taking lumacaftor and combined therapy and usually resolves without stopping treatment. Lumacaftor is a strong inducer of CYP3A while ivacaftor is a CYP3A sensitive substrate. Combination therapy can decrease systemic exposure of medications that are substrates of CYP3A, decreasing therapeutic effect. Co-administration of lumacaftor-ivacaftor with sensitive CYP3A substrates or CYP3A substrates with narrow therapeutic index is not recommended. Expert opinion: Lumacaftor-ivacaftor therapy may be associated with ocular and hepatic side effects. Specific recommendations for monitoring are available. Dyspnea occurs, especially during initiation of treatment. Potential drug interactions should be evaluated in patients taking combination therapy. The risk benefit ratio of lumacaftor-ivacaftor favors therapy.

Background: Clinical trials of 7% hypertonic saline (HTS) in cystic fibrosis (CF) show short-and long-term benefits, including improved pulmonary function and reduced exacerbation risk. Adverse effects of HTS include bronchospasm, and guidelines recommend tolerance be tested in a clinical environment before prescribing. We evaluated the rate of, and risk factors for, intolerance of HTS at a single pediatric CF program. Methods: Single-center retrospective study in patients with CF, aged 6-20 years, who received an HTS test dose between 2006 and 2017. HTS intolerance was defined as either a ‡10% decline in forced expiratory volume in 1 s (FEV 1 ) percent predicted or wheezing/severe cough.Results: Fifty-one patients met inclusion criteria, and 13 (25%) showed intolerance of 7% HTS. There were trends toward higher rates of comorbidities in the patients intolerant versus tolerant of HTS, including allergies and/or rhinitis 85% versus 66% (P = 0.30) and sinus disease 85% versus 58% (P = 0.10). A trend toward more methicillin-sensitive Staphylococcus aureus (58% vs. 31%, P = 0.09) and asthma (42% vs. 24%, P = 0.09) was seen in patients tolerant of HTS. Demographics, pulmonary function, nutritional parameters, laboratory tests, respiratory cultures, chronic therapies, and antibiotics for exacerbations did not differ. Conclusions: In our program, 1:4 children with CF exhibited objective findings of HTS intolerance. There were trends suggesting higher frequency of allergies and rhinosinusitis in intolerant children. Assessing tolerance of HTS before prescribing chronic daily therapy is important. Larger studies are needed to more accurately define the incidence of intolerance and risk factors.