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Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler)

For updated information, please see Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler).

Update 10/07/2008:  FDA’s Early Communication About an Ongoing Safety Review issued on March 18, 2008 stated that Boehringer Ingelheim, the maker of Spiriva HandiHaler (tiotropium bromide), had conducted a pooled analysis of 29 trials that suggested a small excess risk of stroke (2 cases per 1000) with tiotropium bromide over placebo. FDA has now received preliminary data from UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium), a large, 4-year, placebo controlled clinical trial with Spiriva HandiHaler in approximately 6000 patients with chronic obstructive pulmonary disease (COPD).  The preliminary results of UPLIFT reported by Boehringer Ingelheim to the FDA showed that there was no increased risk of stroke with tiotropium bromide (Spiriva HandiHaler) compared to placebo. 

Two recent publications1, 2 reported increased risk for mortality and/or cardiovascular events in patients who received tiotropium or inhaled anticholinergics. Both studies examined cardiovascular outcomes. Singh et al.1 performed a systematic review and meta-analysis of 17 clinical trials enrolling 14,783 patients treated with inhaled anticholinergic drugs used for the treatment of chronic obstructive lung disease. Lee et al.2 performed a case-control study of 32,130 patients (320,501 controls) treated with inhaled medications, including an anticholinergic, for the treatment of chronic obstructive lung disease.

FDA expects to receive the complete report for UPLIFT in November 2008.  Results from this trial will also help to address some issues raised about tiotropium in the two recent publications. Due to the amount of data collected in UPLIFT, a complete review of the results could take several months, at which time FDA will update this communication with the final results of the UPLIFT analysis, as well as all the available data regarding tiotropium and stroke risk.

1. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease.  JAMA 2008; 300 (12): 1439-1450.

2. Lee TA, Pickard S, et al.  Risk of Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease.  Annals of Internal Medicine 2008; 149: 380-390. 

This information reflects FDA’s current analysis of available data concerning this drug.  Posting this information does not mean that FDA has concluded there is a causal relationship between the drug product and the emerging safety issue.  Nor does it mean that FDA is advising health care professionals to discontinue prescribing this product.  FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action.  FDA intends to update this document when additional information or analyses become available. 

The manufacturer of Spiriva HandiHaler, Boehringer Ingelheim, recently informed the FDA that ongoing safety monitoring has identified a possible increased risk of stroke in patients who take this medicine.  Spiriva HandiHaler contains tiotropium bromide and is used to treat bronchospasm associated with chronic obstructive pulmonary disease (COPD).  Additional information is needed to further evaluate this preliminary information about stroke in patients who take Spiriva HandiHaler. 

Boehringer Ingelheim reported to the FDA that it has conducted an analysis of the safety data from 29 placebo controlled clinical studies (“pooled analysis”).  In 25 of the clinical studies, patients were treated with Spiriva HandiHaler.  In the other 4 clinical studies patients were treated with another formulation of tiotropium approved in Europe, Spiriva Respimat.  The 29 clinical studies included approximately 13,500 patients with COPD.  Based on data from these studies, the preliminary estimates of the risk of stroke are 8 patients per 1000 patients treated for one year with Spiriva, and 6 patients per 1000 patients treated for one year with placebo.  This means that the estimated excess risk of any type of stroke due to Spiriva is 2 patients for each 1000 patients using Spiriva over a one year period.

It is important to interpret these preliminary results with caution.  FDA has not confirmed these analyses.  Pooled analyses can provide early information about potential safety issues.  However, these analyses have inherent limitations and uncertainty that require further investigation using other data sources.  This early communication is in keeping with FDA’s commitment to inform the public about its ongoing safety reviews of drugs.

FDA is working with Boehringer Ingelheim to further evaluate the potential association between Spiriva and stroke.  FDA has requested additional information and is currently reviewing post-marketing adverse event reports with Spiriva.  In addition, the manufacturer of Spiriva has conducted a large study called UPLIFT (Understanding the Potential Long-Term Impacts on Function with Tiotropium), which is a large four year study that will provide additional long term safety data with Spiriva and additional insight into the risk of stroke or other safety findings with tiotropium.  The data from UPLIFT is expected to be available in June 2008.  Once Boehringer Ingelheim provides FDA with the UPLIFT study data, FDA will analyze the data and communicate its conclusions and recommendations to the public.

Spiriva HandiHaler is an effective medicine that is indicated for the long-term, once daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.  Patients should not stop taking Spiriva HandiHaler before talking to their doctor if they have questions about this new information.

The FDA urges both healthcare professionals and patients to report side effects from the use of Spiriva HandiHaler to the FDA's MedWatch Adverse Event Reporting program, using the contact information at the bottom of this page. 


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