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July 2012 www.PharmacyTimes.com 105 December 2015 PharmacyTimes.org 105 ivacaftor improved pulmonary function. Additional questions were posed, includ- ing what would the optimal dose for lumacaftor and ivacaftor be for patients homozygous for F508del. Alternative dosing strategies were studied in 1122 subjects aged 12 years or older who were homozygous for the F508del mutation. 51 There were 3 arms to the study: placebo, lumacaftor 600 mg once daily, or lumacaftor 400 mg every 12 hours. Subjects randomized to the lumacaftor study arms were also taking ivacaftor 250 mg every 12 hours. Treatment with lumacaftor and iva- caftor resulted in change in the predicted FEV 1 of 2.6% to 4.0%. Additionally, the rate of pulmonary exacerbations in the treatment arms was 30% to 39% lower than in the placebo arm. Secondary end points evaluating BMI and the CF Questionnaire-revised favored treatment with lumacaftor and ivacaftor. Lumacaftor and Ivacaftor The FDA approved lumacaftor/ivacaftor (Orkambi) in July 2015 for individuals with CF aged 12 years or older with 2 copies of the F508del mutation. 52 Dosing for this therapy can be found in Table 4. 47,52 As with ivacaftor, appropriate counseling and monitoring is required for this therapy. Lumacaftor is a potent CYP3A induc- er. 52 Coadministration of lumacaftor/iva- caftor with therapies that are CYP3A substrates should be evaluated for drug interactions. Agents that have a narrow therapeutic index and are CYP3A sub- strates, such as many immunosuppressive agents, should be avoided in individuals taking lumacaftor/ivacaftor. Additionally, women who are prescribed a hormonal contraceptive and are taking lumacaftor/ ivacaftor should be counseled regarding the decreased hormonal contraceptive exposure, which results in decreased effi- cacy. As previously described, ivacaftor is a CYP3A substrate, and the same drug interactions must be evaluated in patients initiated on lumacaftor/ivacaftor; therefore, pharmacists should complete a patient medication history prior to initiat- ing therapy, periodically assess for drug interactions, and recommend dose adjust- ments accordingly. Safety data showed that the incidence of AEs was similar among individuals in the lumacaftor/ivacaftor and the placebo groups. 51 AEs reported more commonly in the lumacaftor/ivacaftor group includ- ed dyspnea and chest tightness. These respiratory events were typically reported as mild and resolved within 3 weeks of therapy initiation. There was an inci- dence of increased liver enzymes, with an upper limit of normal greater than 3 times in 5.2% in subjects in the lumacaftor/ ivacaftor group, which was similar to the placebo group. Secondary to eleva- tions in liver enzymes, close monitoring of hepatic transaminases is warranted. 52 For individuals initiated on therapy, liver function testing should be performed every 3 months for the first year of therapy and annually thereafter. If during monitoring the alanine aminotransferase level or the aspartate aminotransferase level increases to greater than 5 times the upper limit of normal, therapy should be temporarily discontinued until the trans- aminitis has resolved. Additionally, if the alanine aminotransferase level or the aspartate aminotransferase level increas- es to greater than 3 times the upper limit of normal and there is an elevation in the total bilirubin of greater than 2 times the upper limit of normal, therapy should be temporarily discontinued until the transa- minitis has resolved. VX-661 Research continues to target the underly- ing defect in the CFTR protein leading to the manifestations of CF. Clinical trials are underway for VX-661, a corrector, in individuals homozygous and heterozy- gous for the F508del mutation. One such study is looking at subjects who have 1 copy of F508del and a second gating mutation that was clinically responsive to ivacaftor therapy. 53 Ataluren Ataluren is considered an activator, or read-through agent. 13,42 Class I mutations are the nonsense mutations, and transla- tion of the CFTR protein is stopped once the ribosome reads through a premature stop codon. Treatment with ataluren will allow for the ribosome to complete trans- lation and produce a functional CFTR protein. A small phase 2 study evaluated 2 TABLE 4: CFTR THERAPIES AND DOSING STRATEGIES 47,52 Agent Dosage Form Dose Administration Instructions Ivacaftor (Kalydeco) 50-mg oral granule 2-5 years of age and <14 kg: 50 mg Every 12 hr with a fat-containing food 75-mg oral granule 2-5 years of age and ≥14 kg: 75 mg 150-mg tablet 6 years or older: 150 mg Lumacaftor/ivacaftor (Orkambi) 200/125 mg tablet 12 years or older: 400/250 mg Every 12 hr with a fat-containing food