Tiotropium Bromide Inhalation Powder (Spiriva)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved the first once-daily, quaternary ammonium, anticholinergic bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD). Tiotropium is 10-fold more potent than ipratropium bromide and has a much longer duration of action.1 It is manufactured by Boehringer Ingelheim Pharmaceuticals, Inc and co-marketed by Boehringer Ingelheim and Pfizer as Spiriva.
Indications
Tiotropium is indicated for long-term maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema.2
Dosage
The recommended dose is 1 capsule inhaled once daily with the HandiHaler inhalation device. Each capsule contains 18 mg of tiotropium. No dosage adjustment is needed in patients with renal or hepatic impairment, although patients with moderate-to-severe renal impairment should be monitored closely.2
Potential Advantages
Tioprotium is administered once daily compared to 4 times a day for ipratropium. Trough pulmonary function with tiotropium (ie, mean predose morning FEV1), the primary end point, was statistically superior to ipratropium (administered 4 times a day) and salmeterol (administered twice daily).1,3,5
Potential Disadvantages
Dry mouth is the most common side effect, and the frequency is higher than with ipratropium (12.1% vs 6.1%).3 This was more common in older patients and in women.7 Other side effects include urinary effects and constipation. A higher percent of patients on tiotropium compared to ipratropium had "marked" elevation of LDH.7
Comments
Tiotropium is the first quaternary ammonium anticholinergic drug approved since ipratropium. It has similar affinity for the muscarinc receptor subtypes, M1, M2, and M3. However, its slow dissociation (about 100 times more slowly than ipratropium) from M1 and M3 contributes to its long duration of action.1 Six phase III studies supported the approval of the drug. Four were 1-year studies (2 US and 2 European), and 2 were 6-month multinational studies.3-7 The combined study population was 2663—1308 randomized to tiotropium and the rest to placebo or active control (ipratropium or salmeterol). Patients had relatively stable COPD with FEV1 < 60%-65% of predicted, FVC < 70%, at least 40 years of age, and a smoking history of > 10 pack-years. The primary end point was change from baseline in mean morning predose FEV1 value. Other end points included health-related quality-of-life instruments (St. George’s Respiratory Questionnaire and SF36), COPD exacerbation, COPD hospitalization, and dyspnea. As expected based on its duration of action, tiotropium showed statistically significant improvement in mean morning predose FEV1 compared to placebo and active controls. The mean difference in trough FEV1 response ranged from 110 to 180 mL. Mean peak response ranged from 250 to 310 mL.7 In 1 of the 2 comparative studies tiotropium showed a reduction in the rate of COPD exacerbation compared ipratropium although the published combined results favored tiotropium.3,7 A similar pattern was seen with 2 placebo-controlled studies.5,7 In general, there was no clear, consistent, clinical superiority in terms of the other end points over comparators such as ipratropium or salmeterol, although some numerical advantages were noted.
Tiotropium appears to be well tolerated, and tachyphylaxis was not evident in 1-year studies.1 Boehringer Ingelheim also sought an indication for the relief of dypsnea related to COPD. However, the FDA concluded that data did not support this proposed indication.7 Tiotropium is expected to be available mid-year. Cost is not available at this time.
Clinical Implications
COPD affects more than 5% of the adult population, and its mortality and morbidity is increasing.8 Bronchodilators are standard pharmacological therapy. These include short- and long-acting beta agonists and short-acting anticholinergic. The introduction of tiotropium offers a long-acting anticholinergic bronchodilator with more convenient dosing.
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.
References
1. Hvizdos KM, Goa Kl. Drugs. 2002;62(8):1195-1203.
2. Spiriva® Product Information. Boehringer Ingelheim Pharmaceutical Inc, February 2004.
3. Vincken W, et al. Eur Respir J. 2002;19(2):209-216.
4. Donohue JF, et al. Chest. 2002;122(1):47-55.
5. Brusasco V, et al. Thorax. 2003;58:399-404.
6. Tashkin D, Kesten S. Chest. 2003;123:1441-1449.
7. www.fda.gov/ohrms/dockets/ac/02/briefing/3890B1_05_Clinical%20Briefing.pdf
8. Sin DD, et al. JAMA. 2003;290(17):2301-2312.
The FDA has approved the first once-daily, quaternary ammonium, anticholinergic bronchodilator for the treatment of chronic obstructive pulmonary disease.
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