Tiotropium Soft Mist Inhaler: Should it Receive FDA Approval?

Tiotropium bromide has been a pivotal drug for the maintenance treatment of bronchospasm associated with COPD. The agent, approved in 2004, is delivered via the HandiHaler device and is administered as two inhalations of the powder content of a single capsule once daily. Tiotropium has undergone clinical assessment of delivery by a new method (soft mist inhaler). The soft mist inhaler is a spring loaded delivery system that aerosolizes the intended drug to produce a small micron sized particle to increase efficiency of drug delivery to the pulmonary system. In the U.S., ipratropium bromide/albuterol (Combivent) has been reformulated and is administered by this device. At the present time, 55 countries have approved this device.

Results of a recent U.S. Food and Drug Administration Pulmonary-Allergy Drugs Advisory Board assessed the efficacy and safety data of the new formulation of tiotropium including data from the TIOSPIR trial which enrolled 17,135 patients. Although there was no significant difference in all-cause mortality between the tiotropium arm and placebo there was a small difference in the rates of heart attacks. In addition, the panel reviewed other data including the 2011 systemic review in the British Medical Journal analyzing 5 clinical trials encompassing 6,522 patients to determine if there was a mortality risk of tiotropium administered by the soft mist inhaler for symptomatic improvement in COPD. Tiotropium was associated with a 52% higher risk for all-cause mortality compared to placebo. Potential theories of cardiovascular events may be associated with higher toxicity associated with the soft mist inhaler device. Compared to the 18 mcg delivered by the HandiHaler, 5 mcg delivered by the soft mist inhaler achieved 35% higher peak plasma concentrations and the 10 mcg delivered by mist produced 3-fold higher peal plasma concentrations.¹ Based upon the results of analyzing the data the advisory board voted 10-3 in favor of approval.²

Since many drugs over the years have either been removed from the market or have had black box warnings added to the package insert, do you think tiotropium should be approved in the U.S.? Based upon data identifying cardiovascular risk/mortality, however not statistically significant, would you feel comfortable in having a family member with cardiovascular disease prescribed this agent? Comments are indeed welcome.

Michael J. Cawley, PharmD, RRT, CPFT, FCCM, is a Professor of Clinical Pharmacy at the Philadelphia College of Pharmacy, University of the Sciences. He has greater than 25 years of experience practicing in the areas of medical, surgical, trauma, and burn intensive care as both a critical care clinical pharmacist and registered respiratory therapist.

References:

1. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive lung disease: systematic review and meta-analysis of randomized controlled trials. BMJ 2011;342:d3215.

2. Smith M. FDA Panel Greenlights COPD Mist Drug. Medpage Today. www.medpagetoday.com. 2014 Aug 14.