Brand Name:  Spiriva

Generic Name:  Tiotropium bromide inhalation powder

Manufacturer:  Boehringer Ingelheim Pharmaceuticals, Inc.

Drug Class:  Long-acting, antimuscarinic agent, which is often referred to as an anticholinergic¹

Uses:

·        Labeled

·        Long-term, once-daily maintenance treatment of brochospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema^1-2,4

·        Unlabeled

·                    Dyspnea²

·        Asthma³

Mechanism of Action:  Tiotropium is a long-acting, antimuscarinic agent with similar affinity to the subtypes of muscarinic receptors M₁ to M₅.  It exhibits its pharmacological effects through competitive and reversible inhibition of M₃-receptors at the smooth muscle leading to bronchodilation.^1,4

Pharmacokinetics^1,3,4:

·        Metabolism

·        Approximately 25% of tiotropium is metabolized by the liver through CYP450-dependent (2D6, 3A4) oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites.  Tiotropium is also nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors.^1,4

·        Elimination

·        Intravenously administered tiotropium is mainly excreted unchanged in urine (74%).  After dry powder inhalation, urinary excretion is 14% of the dose, the remainder being mainly non-absorbed drug in the gut which is eliminated via the feces. 

·        The renal clearance of tiotropium exceeds the creatinine clearance, indicating active secretion into the urine.^1,4

Efficacy:

• Casaburi R, Mahler DA, Jones PW, et al.  A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.  Eur Respir J.  2002 Feb;19(2):217-24.

·        Study design – randomized, double-blind, placebo-controlled, prospective, multicenter, intent-to-treat, 1-year study

·        Description – Patients with stable COPD (age 65.2±8.7 years (mean±SD), n=921) were enrolled in two identical 1-year studies.  Patients inhaled tiotropium 18 mcg (n=550) or placebo (n=371) once daily as a dry powder.  The primary spirometric outcome was trough forced expiratory volume in one second (FEV₁) (i.e., FEV₁ prior to dosing).  Medication use and adverse events were recorded.  Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV₁ response (~12% over baseline) (p<0.01) and mean response during the 3 hours following dosing (~22% over baseline) (p<0.001) over the 12-month period.  Tiotropium recipients showed less dyspnea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations relative to placebo (p<0.05).  Adverse events were comparable to placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05).

·        Limitations – The study was supported by Boehringer Ingelheim Pharmaceuticals, Inc.  Three of the authors are employees of Boehringer Ingelheim Pharmaceuticals, Inc.  No confidence intervals were reported.  Patients were required to have clinically stable airway obstruction, so results cannot be extrapolated to patients with unstable COPD.  Power and limitations were not addressed by the authors.

·        Conclusions – The authors concluded that tiotropium is an effective, once-daily broncodilator that reduces dyspnea and COPD exacerbation frequency and improves health status.  These authors also concluded that this study suggests that tiotropium will make an important contribution to COPD therapy.  I believe that this study was conducted reasonably fairly and that tiotropium is an effective treatment for COPD.  However, more studies are necessary to confirm these results and the role of tiotropium in COPD therapy.

• Littner MR, Ilowite JS, Tashkin DP, et al.  Long-acting bronchodilation with once-daily dosing of tiotropium (spiriva) in stable chronic obstructive pulmonary disease.  Am J Respir Crit Care Med.  2000 Apr;161(4 Pt 1):1136-42.

·        Study design – randomized, double-blind, placebo-controlled, prospective, parallel-group, multicenter, 29-day study

·        Description – This study was designed to evaluate the dose-response characteristics of tiotropium inhalation powder given once daily to stable patients with COPD.  Patients (n=169) were randomized to receive 0, 4.5, 9, 18, or 36 mcg tiotropium (n=35, 34, 33, 33, 34, respectively) once daily at noon for 4 weeks, with spirometry done before and hourly for 6 hours after dosing.  Significant dose-related improvement in FEV₁ and forced vital capacity (FVC) occurred within 1 hour after the first dose of tiotropium as compared with placebo.  All doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20-24 hours after the previous dose and just before the next dose of triotropium), peak, and 6-hour postdose average FEV_1, FVC, and peak expiratory flow rate (PEFR) without a significant difference among the different doses investigated (p<0.05).  The overall safety profile for tiotropium was similar to that for placebo. 

·        Limitations – The study was supported by Boehringer Ingelheim Pharmaceuticals, Inc.  Author affiliations, power, confidence intervals, and limitations were not reported.  Patients measured and recorded their own PEFRs.  Patients were required to have relatively stable, moderate-to-severe airway obstruction, so results cannot be extrapolated to patients with unstable COPD.  Patients were excluded if they had another “significant disease.”  There was a short study duration of 29 days.  There was not an intent-to-treat analysis, and missing data were estimated.

·        Conclusions – The authors concluded that tiotropium was shown to be safe and effective in doses ranging from 4.5-36 mcg delivered once daily.  I believe that this study suggests the safety and efficacy of tiotropium across a range of doses, although tiotropium is only available and approved for one dose.  However, numerous limitations require further studies to verify these results.

• Donohue JF, van Noord JA, Bateman ED, 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 Jul;122(1):47-55.

·        Study design – randomized, double-blind, double-dummy, placebo-controlled, prospective, multicenter, multinational, parallel-group, 6-month study

·        Description – This trial was designed to examine the efficacy and safety of tiotropium and salmeterol with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD.  A total of 623 patients participated and received either 18 mcg tiotropium daily via dry powder inhaler (n=209), salmeterol 50 mcg bid via metered-dose inhaler (n=213), or placebo (n=201).  Compared with placebo treatment, the mean predose morning FEV₁ following 6 months of therapy increased significantly more for the tiotropium group than for the salmeterol group (p<0.01).  The average FEV₁ (0-12 hours) for tiotropium was statistically superior to salmeterol (p<0.001).  Tiotropium also proved statistically superior to salmeterol and placebo in several other categories.

·        Limitations – This study was supported by Boehringer Ingelheim Pharmaceuticals, Inc.  Four of the authors have been consultants for Boehringer Ingelheim Pharmaceuticals, Inc.  Patients were required to have relatively stable airway obstruction, so results cannot be extrapolated to patients with unstable COPD.  Patients were excluded if they had another “significant disease,” which was decided by the investigator.  Patients measured and recorded their own peak flow rates, rescue medication use, and PEFRs.  This study did not use an intent-to-treat analysis, and missing data were estimated.  No confidence intervals or limitations were reported by the authors.

·        Conclusions – The authors concluded that tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.  The authors also concluded that tiotropium can be considered as an appropriate first-line therapy for patients experiencing symptomatic COPD.  I disagree with the authors’ statement that tiotropium is first-line for symptomatic COPD because this trial had excessive limitations that need to be addressed with further unbiased trials.

Contraindications: 

·        Patients with a history of hypersensitivity to atropine or its derivatives, including ipratropium, or to any component of this product^1,4

Warnings:

·        Spiriva is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).

·        Immediate hypersensitivity reactions, including angioedema, may occur after administration.  If such a reaction occurs, therapy with Spiriva should be stopped at once, and alternative treatments should be considered.^1,4

Precautions:

·        Spiriva may potentially worsen symptoms and signs associated with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction and should be used with caution in patients with any of these diseases.

·        Patients with moderate to severe renal impairment (creatinine clearance of 50 mL/min or less) treated with Spiriva should be monitored closely.^1,4

Pregnancy:

·        Pregnancy category C

·        There are no adequate and well-controlled studies in pregnant women.

·        Spiriva should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.^1,4

Lactation:

·        Clinical data from nursing women exposed to tiotropium are not available.

·        Animal studies show that tiotropium is excreted into breast milk.

·        Caution should be exercised if Spiriva is administered to a nursing woman.^1,4

Adverse Effects^1-4:

·        ³3%

·        dry mouth

·        constipation

·        increased heart rate

·        blurred vision

·        glaucoma

·        urinary difficulty

·        urinary retention

·        1-3%

·        allergic reaction

·        leg pain

·        dysphonia

·        paresthesia

·        gastrointestinal disorder not otherwise specified

·        gastroesophageal reflux

·        stomatitis (including ulcerative stomatitis)

·        hypercholesterolemia

·        hyperglycemia

·        skeletal pain

·        angina pectoris (including aggravated angina pectoris)

·        depression

·        herpes zoster

·        laryngitis

·        cataract

Drug Interactions:

·        Other anticholinergic drugs (e.g., ipratropium) – co-administration with tiotropium has not been studied^1-4

Dosing/Administration:

·        The recommended dosage is the inhalation of the contents of one Spiriva capsule (18 mcg tiotropium), once-daily, with the HandiHaler inhalation device.

·        The safety and effectiveness of Spiriva in pediatric patients have not been established.

·        No dosage adjustment is required for geriatric, hepatically-imparied, or renally-impaired patients.  However, patients with moderate to severe renal impairment given Spiriva should be monitored closely.^1,4

Overdosage:

·        Acute intoxication by inadvertent oral ingestion of Spiriva capsules is unlikely since it is not well-absorbed systemically.

·        High doses of tiotropium may lead to anticholinergic signs and symptoms.^1,4

Storage:

·        Store at 25°C (77°F); excursions permitted to 15-30° (59-86°F).^1,4

Conclusion:

·        Spiriva is a relatively new drug which is lacking thorough long-term safety and efficacy studies.  Spiriva has an advantage over other anticholinergics such as ipratropium because of its once daily dosing.  Despite one trial considering Spiriva first-line therapy for COPD, more studies are needed to validate this conclusion.  However, Spiriva seems to be an effective, well-tolerated therapy for COPD in spite of the relative deficiency in research.

References:

1.      Spiriva Package Insert.  Boehringer Ingelheim Pharmaceuticals, Inc; Pfizer.  Referenced from http://www.bidocs.com/renetnt:/Prescribing%20Information/PIs/Spiriva/Spiriva.pdf?DMW_FORMAT=pdf.  [Accessed 10-29-04].

2.      Clinical Pharmacology:  Spiriva.  2004.  Gold Standard Multimedia.  Referenced from http://cpip.gsm.com.soleproxy.hsc.wvu.edu/.  [Accessed 10-29-04].   

3.      Editorial Staff:  Spiriva.  DRUGDEXÒ System.  MICROMEDEX.  Greenwood Village, Colorado (Edition expires 12-2004).

4.      Mosby’s Drug Consult:  Tiotropium.  2004.  Mosby, Inc.  Referenced from http://home.mdconsult.com/das/drug/view/42198878-2/1/4031/top?sid=313332745.  [Accessed 10-29-04].

5.      Casaburi R, Mahler DA, Jones PW, et al.  A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.  Eur Respir J.  2002 Feb;19(2):217-24.

6.      Littner MR, Ilowite JS, Tashkin DP, et al.  Long-acting bronchodilation with once-daily dosing of tiotropium (spiriva) in stable chronic obstructive pulmonary disease.  Am J Respir Crit Care Med.  2000 Apr;161(4 Pt 1):1136.

7.      Donohue JF, Van Noord JA, Bateman ED, 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 Jul;122(1):47-55.