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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved two drugs for the treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone is an antifibrotic agent and nintedanib is a tyrosine kinase inhibitor. Both products were approved on a fast-track priority review, with orphan status and breakthrough designation. Pirfenidone is marketed by InterMune as Esbriet and nintedanib as Ofev by Boehringer Ingelheim.
Both drugs are approved for the treatment of idiopathic pulmonary fibrosis.1,2
Pirfendone — the recommended dose is three capsules (801 mg) three times daily with food.1 The dose should be titrated according to the following schedule: one capsule three times a day the first 7 days, two capsules three times a day through day 14, and three capsules daily thereafter.
Pirfendone is available as 267 mg capsules.
Nintedanib — the recommended dose is 150 mg twice daily, approximately 12 hours apart with food.2 To manage adverse events, the dose may be reduced to 100 mg, or dosing may be temporarily interrupted or even discontinued.
Nintedanib is available as 100 mg and 150 mg capsules.
Pirfenidone and nintedanib represent drugs with new mechanisms of action for the treatment of IFD.
Common adverse events (% vs placebo) for pirfenidone are nausea (36% vs 16%), rash (30% vs 10%), abdominal pain (24% vs 15%), and dyspepsia (19% vs 7%). Common adverse events for nintedanib are diarrhea (62% vs 18%), nausea (24% vs 7%), and abdominal pain (15% vs 6%). Both drugs are associated with an increase in liver enzymes. Nintedanib is not recommended for patients with moderate or severe liver impairment.1,2 Pirfenidone is not recommended for severe liver impairment. Pirfenidone is associated with photosensitivity and rash while nintedanib is embryotoxic.
The safety and efficacy of both pirfenidone and nintedanib were evaluated in subjects with clinically confirmed IPF. Other eligibility criteria were forced viral capacity (FVC) at 50% or more of predicted, and diffusion capacity of lung for carbon monoxide (DLCO) of at least 30% predicted.1,2,3,4 At baseline, the pirfenidone subjects had a mean FVC % of predicted of approximately 68%, compared to 81% for the nintedanib subjects. DLCO % of predicted were approximately 44% and 47%, respectively. The primary efficacy endpoint was decline in FVC. However, this was measured differently between drugs. For pirfenidone, it was the proportion of subjects who had a decline of >/= 10% from baseline to week 52 in the percentage of predicted FVC or who had died. The nintedanib study measured the annual rate of decline in FVC. Pirfenidone was evaluated in three placebo-controlled studies: two showed positive results and the third showed no difference in decline of FVC.1 For study one (ASCEND) (n = 555), 17% of those randomized to pirfenidone met the endpoint compared to 32% for placebo (47% reduction). Study two showed similar results. For nintedanib, efficacy and safety were evaluated in two Phase 3 placebo-controlled studies (n = 513, 548).2,4 Rates of decline in FVC were -115 mL for study one and -114 mL for study two, compared to -240 and -207, respectively, for placebo. The differences vs. placebo were -125 (95% confidence interval [CI], 78-173) and -94 mL (95% CI, 45-143). It is difficult to compare cross studies to try to glean potential differences, but using the pirfenidone endpoint, the 10% decline in FVC for nintedanib was 28% vs 43% for placebo (35% reduction).2 Based on the studies cited in the respective labels, no statistically significant differences in all-cause mortality were observed for either drug. However, when data were pooled from two Phase 3 studies, survival significantly favored pirfenidone.3
IPF is a chronic, progressive, and fatal lung disease characterized by a decline in lung function due to proliferation of fibrous tissue in the lungs. Previous treatment, with limited effectiveness, includes prednisone, azathioprine, and N-acetyl cysteine.5 Pirfenidone and nintedanib are the first FDA-approved treatments for IDF. These drug are effective in slowing the progression of the disease as measured by the decline in FVC. It is not clear whether one drug offers any clear advantage over the other, although some difference may emerge with more clinical experience. The wholesale cost for pirfenidone is $7800 for 30 days and for nintedanib is $8000 for 30 days for both the 100 mg and 150 mg doses.