Vol. VII, No. 3
  May/June 2004

  Katie Milner, Pharm.D.

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Spiriva® HandiHaler® (Tiotropium) - A New Therapy for COPD

Introduction: The use of inhaled anticholinergic medications in the treatment of chronic obstructive pulmonary disease (COPD) is one of the focal recommendations by the current Global Initiative for Chronic Obstructive Lung Disease guidelines.¹ Ipratropium (Atrovent®), is a widely administered agent in COPD and the only previously available inhaled anticholinergic agent. It has been shown to reverse the increased cholinergic tone occurring in COPD, resulting in desired bronchodilation.² A problem with ipratropium use, however, is compliance, as it has a short duration of action that requires administration four times daily.

In February 2004, tiotropium (Spiriva® HandiHaler®) received approval by the Food and Drug Administration as an inhaled anticholinergic agent. Tiotropium is approved for the long-term, once-daily, maintenance treatment of bronchospasm associated with COPD, including chronic bronchitis and emphysema, which is the same indication as ipratropium. Tiotropium has differences in its pharmacologic and pharmacokinetic properties that may make it a more advantageous anticholinergic agent to ipratropium.

Pharmacology: Tiotropium, a quaternary ammonium derived from ipratropium, is a long-acting nonselective antagonist of the muscarinic receptors M₁ to M₅. Inhibition of the muscarinic receptors block cholinergic neurotransmission causing bronchodilation. Tiotropium's affinity to these receptors is 6- to 20-fold greater than ipratropium.^2,3 Unlike the other muscarinic receptors, blockade of the specific M₂ receptor causes an increase in the release of acetylcholine, which is an unwanted effect. Two pharmacological benefits of tiotropium in comparison to ipratropium are that it dissociates much more rapidly from the M₂ receptor, as well as having prolonged binding to the M₁ and M₃ receptors. The resultant pharmacokinetic effects are a slower onset and longer duration of action than ipratropium.⁴ This is demonstrated as the half-life of the tiotropium-muscarinic receptor complex in human lung tissue is 212 minutes, while the half-life of the ipratropium-muscarinic receptor complex is only 11 minutes.⁵

Pharmacokinetics: The absolute bioavailability of tiotropoium is 19.5% following dry powder inhalation and peak plasma levels are reached within 5 minutes and decline within 1 hour to very low levels.³ Tiotropium accumulates in tissue over time and steady state is reached after about 25 days, with a terminal plasma elimination half-life of 5 to 6 days.⁶ The metabolic pathway of tiotropium differs from that of ipratropium. Tiotropium is non-enzymatically cleaved to inactive compounds, in addition, a portion of the dose is also metabolized via CYP450 2D6 and 3A4 pathways, and then further metabolized via glutathione conjugation to many phase II metabolites. Urinary excretion of tiotropium accounts for 14% of the dose, with the remaining non-absorbed drug eliminated in the feces.³ Patients with renal impairment have been demonstrated to have an increase in tiotropium's area under the curve. Elimination is also reduced in patients with advanced age, likely in association with reduced renal function.

Selected Clinical Trials: A dose-finding, double-blind study of tiotropium in COPD was performed by Littner and colleagues to evaluate the efficacy and safety of multiple doses of tiotropium in patients with a diagnosis of COPD.⁷ One hundred and sixty-nine patients were randomly assigned treatment with placebo or tiotropium 4.5-, 9-, 18-, or 36-mcg once daily via a dry powder inhaler for 4 weeks. There were no dose-dependent increases in adverse events, however, the largest proportion of patients with any adverse event was observed with the 36 mcg dose. On the basis of comparable bronchodilation properties with all of the tiotropium dosages and a more favorable safety profile for dosages less than 36 mcg, the 18 mcg dose was selected for further studies.

Tiotropium was compared to placebo in two trials by Casaburi and coworkers (470 and 921 patients, respectively) and in a trial by Tashkin and colleagues (921 patients).^8-10 These were all randomized, double-blind studies that enrolled patients with stable COPD to evaluate its efficacy and safety. Patients had to be > 40 years of age with a > 10 pack/year smoking history, a forced expiratory volume in 1 second (FEV₁) < 65% of predicted, and a FEV₁ < 70% of the forced vital capacity (FVC). Exclusion criteria included a history of asthma, allergic rhinitis, atopy, or a total blood eosinophil count > 600/mm³, required oxygen therapy, prednisone therapy > 10 mg/day, recent history of myocardial infarction, heart failure, or cardiac arrhythmia. Patients received either tiotropium 18 mcg or placebo once daily via a dry powder inhaler. Overall, these studies demonstrated that, in comparison to placebo, tiotropium use resulted in statistically and clinically significant increases in the FEV₁ and FVC values. Health outcomes evaluated also showed benefit with tiotropium use, specifically demonstrating that the tiotropium group had less COPD exacerbations, better COPD-specific health status scores, better generic health status scores, and less albuterol use. It was concluded that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as maintenance therapy in COPD.

Tiotropium was also compared to the standard, inhaled, anticholinergic agent ipratropium in two randomized, double-blind trials by Van Noord and coworker (288 patients) and Vinken and colleagues (535 patients).^11,12 The trials enrolled patients with stable COPD and similar inclusion and exclusion criteria as in the placebo-controlled studies mentioned previously. Patients were randomized to therapy with either tiotropium 18 mcg once daily or ipratropium 40 mcg four times daily. Combining the results of both trials, tiotropium was associated with greater improvement in lung function. Specifically, trough, average, and peak FEV₁ levels as well as average FVC levels in the tiotropium-treated patients were associated with greater improvement. The tiotropium group was also associated with greater improvement in symptoms of dyspnea, fewer COPD exacerbations, improved scores from a quality of life questionnaire, and better COPD-specific health status scores in comparison to ipratropium. The authors concluded that tiotropium was effective in improving dyspnea, exacerbations, health-related quality of life, and lung function in patients with COPD, and exceeds the benefits previously documented with ipratropium.

Finally, tiotropium was also compared to the long-acting beta₂-agonist salmeterol (Serevent®) in two randomized, double-blind, placebo-controlled trials by Donohue and coworkers (623 patients) and Brusasco and colleagues (1207 patients).^13,14 These studies compared tiotropium 18 mcg once daily via a dry powder inhaler with salmeterol 50 mcg twice daily via a metered-dose inhaler and placebo in patients with stable COPD. COPD was defined as an FEV₁ < 60% of predicted normal and an FEV₁ < 70% of FVC. Additional inclusion criteria included patients > 40 years of age with a smoking history of > 10 pack/year. Patients were excluded if they had a history of asthma, allergic rhinitis or atopy, an elevated total eosinophil count, or a recent respiratory tract infection. Tiotropium was associated with greater improvement in trough FEV₁ and FVC, peak FEV₁, and average FEV₁ when compared with salmeterol or placebo. The various health outcome endpoints that were evaluated demonstrated that tiotropium delayed the time to first COPD exacerbation versus salmeterol and placebo, although the exacerbation rate did not differ between the tiotropium and salmeterol groups. Additionally, tiotropium-treated patients had greater improvement in dyspnea than either the salmeterol- or placebo-treated patients, fewer COPD exacerbations and fewer exacerbation days per patient year than in placebo-treated patients, and improvement of the COPD-specific health status score. It was concluded from these trials that tiotropium produces better bronchodilation and improvements in dyspnea compared to salmeterol in patients with COPD.

Adverse Effects and Drug Interactions: The primary adverse effect of tiotropium is dry mouth. This effect has been found to be generally mild and resolves with continued therapy.³ The peak incidence has been reported to occur after 3 to 4 weeks of therapy, when steady-state concentrations are reached. In a study comparing tiotropium once daily from a dry powder inhaler and ipratropium four times daily from a metered-dose inhaler, the only drug-related adverse effect was dry mouth, which occurred in 14.7% of tiotropium-treated patients and 10.3% of ipratropium-treated patients.¹¹ Other adverse effects reported with therapy have included chest pain, fatigue, headache, dizziness, hypoesthesia, abdominal pain, constipation, diarrhea, pain, COPD exacerbation, cough, pharyngitis, sinusitis, influenza-like symptoms, upper respiratory tract infection, and pneumonia.^8,11 In most studies, tiotropium was not reported to affect heart rate or blood pressure, even at doses up to 281 mcg.¹⁵

Tiotropium has been coadministered with other commonly used medications in COPD (e.g., sympathomimetic bronchodilators, methylxanthines, and oral or inhaled corticosteroids) without an increase in adverse drug reactions. Tiotropium has not been studied with other anticholinergic agents and concomitant administration with such agents is not recommended.³

Pregnancy and Lactation: Tiotropium is classified as a pregnancy risk category C. A pregnancy risk category C has either demonstrated adverse effects on the fetus of animals and there are no controlled studies in women, or studies in women and animals are not yet available. Drugs in pregnancy risk category C should only be if given if the potential benefit justifies the potential risk to the fetus. Clinical data from nursing women are not yet available, and based on lactating rodent studies, tiotropium is excreted in human milk. Caution should, therefore, be exercised if tiotropium is administered to a nursing woman.^3,16

Dosing and Administration: Tiotropium is administered as a single daily 18 mcg capsule dose via a HandiHaler® dry powder inhaler. For administration, a capsule is placed into the center chamber of the HandiHaler® device. Pressing and releasing the button on the side of the inhalation device pierces the capsule and the tiotropium is dispersed into the air stream when the patient inhales through the mouthpiece. Patients should be instructed to inhale slowly and deeply for a total of two breaths to assure that all of the capsule's contents have been removed.

Cost: Packages of tiotropium are available containing six capsules and one HandiHaler® device (for hospital- or short-term use) or 30 capsules and one HandiHaler® device (for long-term use). The average wholesale price (AWP) for the tiotropium package of 30 capsules is $117.12 and the package of 6 capsules is $31.72.¹⁷

Formulary Status: Tiotropium (Spiriva®) is on the CCF Formulary of Accepted Drugs.

Conclusion: Tiotropium appears to be an effective bronchodilator in the therapy of COPD. It has been demonstrated to have a greater efficacy on lung function and health outcomes than ipratropium. The side effect profile of tiotropium is similar to ipratropium, except for a higher incidence of dry mouth. An additional and practical benefit of tiotropium is its decreased frequency of administration. Once-a-day administration with tiotropium is likely to improve compliance compared to four-times daily administration required with ipratropium therapy.

References:

1. Pauwels R, Anthonisen N, Bailey WC, Barnes PJ, Buist AS, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease executive summary, updated 2003. National Heart, Lung, and Blood Institute-World Health Organization workshop report 2003. Available from http://www.goldcopd.com/docs.html. Accessed 5/27/2004.
2. Panning CA, DeBisschop M. Tiotropium: an inhaled, long-acting anticholinergic drug for chronic obstructive pulmonary disease. Pharmacotherapy 2003;23(2):183-9.
3. Tiotropium (Spiriva® HandiHaler®) package insert. Ridgefield, CT: Boehringer Ingelheim Pharma GmbH; January 2004.
4. Takahashi T, Belvisi MG, Patel H, Ward JK, Tadjkarimi S, Yacoub MH, et al. Effect of Ba 679 BR, a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways. Am J Respir Crit Care Med 1994;150:1640-5.
5. Haddad E-B, Mak JC, Barnes PJ. Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: Radioligand binding and autoradiographic mapping. Mol Pharmacol 1994;45:899-907.
6. Disse BG. The pharmacokinetic (PK) profile of tiotropium during long term treatment in stable COPD. Am J Respir Crit Care Med 1999;159(3):A524 (abstract C24).
7. Littner MR, Ilowite JS, Tashkin DP, Friedman M, Serby CW, Menjoge SS, et al. Long-acting bronchodilatation with once-daily dosing of tiotropium (Spiriva®) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1136-42.
8. Casaburi R, Briggs DD, Donohue JF, Serby CW, Menjoge SS, Witek TJ. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD. A 13-week multicenter trial. Chest 2000;118:1294-1302.
9. Casaburi R, Mahler DA, Jones PW, Wanner A, San PG, ZuWallack RL, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19:217-24.
10. Tashkin D, Kesten S. Long-term treatment benefits with tiotropium in COPD patients with and without short-term bronchodilator responses. Chest 2003;123:1441-9.
11. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ. A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax 2000;55:289-94.
12. Vincken W, van Noord JA, Greefhorst AP, Bantje TA, Kesten S, Korducki L, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J 2002;19:209-16.
13. Donohue JF, van Noord JA, Bateman ED, Langley SJ, Lee A, Witek TJ, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002;122:47-55.
14. Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 2003;58:399-404.
15. O'Connor BJ, Towse LJ, Barnes PJ. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med 1996;154:876-80.
16. Briggs GG, Freeman RK, Yaffe SJ, editors. A reference guide to fetal and neonatal risk drugs in pregnancy and lactation. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2002. p. v11-xxiv.
17. Spiriva®. Cardinal Wholesaler, Inc. Accessed 6/15/04.