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Drug Monograph Generic Name: tiotropium Brand Name: Spiriva Manufacturers: Boehringer Ingelheim, Pfizer Classification: Anticholinergic, Antiasthmatic & COPD Preparations Status: P1S1S3, Prescription only Similar agents: Ipratropium Therapeutic Indications: For the maintenance treatment of chronic obstructive pulmonary disease Pharmacologic data: Bronchial smooth-muscle contraction, the release of mucus into the airway lumen, and possibly the stimulation of ciliary activity, are brought about by parasympathetic activity in the airways, through the M1 and M3 subtypes of muscarinic receptors that are located on the above structures predominantly in large and medium-sized airways.1 In contrast, M2 receptors, which are located on the postganglionic parasympathetic nerves, provide feedback inhibition to inhibit acetylcholine release from those nerve terminals. In theory, therefore, optimal inhibition of parasympathetic activity would be achieved by selective antagonism of the M1 and M3 receptors, sparing the M2 receptors. In both animal and human tissues, tiotropium binds to all three muscarinic receptor subtypes but dissociates rapidly from M2 receptors. The half-life of the receptor-drug complex, an index of the duration of action of the drug, is 35 h in the case of tiotropium on M3 receptors vs 0.3 h for ipratropium.2,3 Evidence-based Clinical Guidelines: Tiotropium is a long acting antimuscarinic bronchodilator that is licensed for maintenance treatment of COPD and it is not suitable for the relief of acute bronchospasm. The updated 2003 GOLD Workshop Report recommend for moderate or severe COPD use of regular treatment of long acting bronchodilator, including tiotropium, rather than short acting bronchodilator.7 For moderate severity of COPD, if insufficient clinical response to ipratropium/Combivant, switch to tiotropium 18 mcg daily with inhaled salbutamol and with or without salmeterol according to the disease severity. Consider, switching back if no improvement. Tiotropium 18 mcg should not be use together with other ipratropium product. The breath 1 actuated inhaler device and capsule may be difficult to use and patient will need individual assessment and counsel if appropriate.8 The clinical applications of long-acting bronchodilator have also been mentioned in the NICE guideline. 9 No significant clinical guideline regarding tiotropium were found in BTS COPD guideline. 10 Inhaled short acting (ipratropium or oxitropium bromide) or long acting (tiotropium) anticholinergic drug is the first line treatment. The dose must be high enough, once a day with the long acting tiotropium. 11 There is also a guideline for the use of tiotropium (Spiriva), with is lack of evidence, but can be use as a reference.12 Suitable Patients • Patients suitable for initiation of tiotropium should have a convincing diagnosis of COPD confirmed by obstructive physiology (moderate or severe: Fev1 <60% of predicted) and irreversibility confirmed by either a <15% response to high dose inhaled bronchodilator challenge or a negative steroid trial. • Patients should have a history of regular smoking or an occupational or genetic cause for a diagnosis of COPD. • Patients should be in a chronic stable condition, so that a response to treatment can be observed. • Patients should have a history of regular exacerbations requiring GP attendance, prescription of antibiotics and or oral steroids or episodes of hospitalization. Unsuitable patients • Tiotropium should NOT be prescribed during a period of acute exacerbation, because a symptomatic response to treatment could not be observed. • Patients with proven or documented asthma should NOT be prescribed tiotropium. • Patients with mild COPD or infrequent exacerbations are unlikely to benefit. Inhaler Device • The inhaler device involves the insertion of a capsule into a dry powder delivery. A degree of manual dexterity is required. • Patients need to be appropriately and adequately educated. Patients with severe arthritis of the hands, tremor or lack of significant muscular control of both hands, are unlikely to be able to use the inhaler device satisfactorily. • There have already been reports of patients swallowing the capsules in belief this was the appropriate means of delivery. Exacerbations of COPD • During exacerbations of COPD, tiotropium should be omitted if nebulised ipatropium is prescribed. Tiotropium should be restarted once the nebuliser has been discontinued. 2 Additional drugs Regular use of Atrovent (including Combivent) should be discontinued if tiotropium is prescribed. Rescue prescription of short-acting beta agonists (but not including anticholinergics) should be continued. It is likely that benefit of tiotropium and salmeterol will be additive, though this has not been proven in trials. No significant drug interactions are known. In conclusion, tiotropium is recommended in carefully selected patients with chronic stable (moderate or severe) COPD, particularly those experiencing regular exacerbations or hospital. Monitor patients for evidence of clinical benefit and discontinue the drug if there is no benefit. Ensure patients are adequately assessed before and after initial prescription to avoid continuing use in non-responsive patients. Clinical studies In all clinical studies reviewed here, tiotropium was administered as a dry powder in a random-assignment, double blind, parallel group, placebo or active-controlled, double-dummy format. Bronchodilation Onset and Duration of Bronchodilation: Following inhalation of single doses of tiotropium, the FEV1 rises relatively slowly, reaching a peak after 1 to 3 h.13, 14 The peak response is followed by a plateau of long duration. Doses from 10 to 80 μg showed only slight differences from each other, all being significantly greater than placebo up to 32 h.14 The dip in FEV1 seen between 16 h and 24 h after dosing is due to the circadian nocturnal dip in airway function that is not entirely abolished by tiotropium.15 An alternative and possibly more rigorous test of the duration of effect of a bronchodilator is to determine how long the agent can protect against a bronchospastic stimulus. In a study16 of 12 atopic, male, asthmatic patients, tiotropium in all doses from 10 to 80 μg provided significant protection against a methacholine challenge for 48 h. These data indicate that the effect of tiotropium on airways physiology persists for up to 48 h and possibly longer. Following repeated daily use of tiotropium, the persistence of bronchodilation from the first day is evident as an increase in the baseline on the next day. The FEV1 23 to 24 h after a dose but before the next dose, its “trough” value, increases over the first few days of regular administration. Van Noord et al 13 found that trough FEV1 increased by 0.19 L (18% above the initial baseline) after 8 days of daily administration, most of this increase having occurred by the second day. Trough FVC continued to rise daily during the first week, increasing by 0.67 L (27% above its initial baseline) by day 8. The elevation in trough values is thought to be clinically important, as it signifies that, with regular daily use, bronchodilation will be maintained around the clock, and that repeated use results in 3 progressive effects above those obtained on a single occasion. Carryover of bronchodilation from one dose to the next has also been observed with long acting β-agonists17; however, these agents must be administered every 12 h. Dose Response: In the dose-response study of Maesen et al 14, effective bronchodilation was found following single administrations of tiotropium at each dose from 10 to 80 μg. To examine the steady state with regular daily dosing, Littner et al 18 performed a dose-response study in which 169 patients with COPD received tiotropium in one of four doses (4.5 to 36 μg qd) or placebo for 28 days. In all treated groups, the trough FEV1 rose to a stable level approximately 0.1 L above the initial baseline value. In the 6 h following the final administration, the FEV1 rose a further 0.12 to 0.2 L above placebo, there being no significant difference between doses. All subsequent studies have used a daily dose of 18 μg. After the conclusion of the active phase of this study, and following withdrawal of tiotropium, the baseline (as measured by twice-daily peak expiratory flow rate) gradually returned to its prestudy level over a period of approximately 3 weeks, indicating the prolonged effect of the drug. Long-term Studies: The long-term efficacy of tiotropium has been studied in three, paired, multicentered trials.19–22 One 1-year paired trial 19 was performed in the United States and compared tiotropium with placebo; another 1-year paired trial 20 was performed in Europe, and compared tiotropium with ipratropium. Two 6-month trials 21,22 compared tiotropium with salmeterol and placebo. In the 1-year studies, patients with moderate-to-severe COPD received tiotropium, 18 μg qd; the control agent was either placebo, 19 or ipratropium, 40 μg qid. 20 Enrollment numbers were 921 patients and 535 patients, respectively. In both studies, the primary outcome was trough FEV1 as described above; secondary outcomes included dyspnea scores, measures of health status, exacerbations of COPD, and adverse events. The baseline FEV1 values were very similar between treatment groups in both studies. Following 8 days of regular treatment, the trough FEV1 was 0.1 L higher than at baseline in the groups that received tiotropium. In both studies, the trough FEV1 of the group that received tiotropium remained at its 8-day level throughout the rest of the trial period, while the trough FEV1 of the control groups remained at or below baseline levels. By the end of both 1-year trials, the difference in trough FEV1 between tiotropium and control groups was 0.15 L. The increases in FEV1 in the first 3 h following administration of agents are observed; these were approximately 0.15 L above trough levels in the case of tiotropium. The results of FVC measurements (not shown) paralleled those of FEV1, with trough levels increasing by 0.26 to 0.32 L with tiotropium. The use of open-label albuterol as “rescue” for breakthrough dyspnea was statistically less in the tiotropium group than in the control group.19, 20 A post hoc analysis 23 of one of these reports 19 concluded that the spirometric response to tiotropium on the first day of treatment 4 did not predict the ability of patients to benefit from longterm treatment with tiotropium. The two 6-month trials 21, 22 employed protocols that were very similar to each other and those of the 1-year studies described above, except that they included an additional patient group that received salmeterol, 50 μg bid, by metered-dose inhaler. The report by Brusasco and colleagues 22 represents an analysis of the two studies combined, and includes 1,207 subjects. In the combined trials, after 6 months of regular treatment, the trough FEV1 values had increased by 0.12 L over the day-1 baseline values with tiotropium (last administered 23 to 24 h previously), and 0.09 L with salmeterol (last administered 11 to 12 h previously), the differences between these two treatments being statistically significant in the pooled analysis. 22 Both the peak and mean FEV1 over the first 3 h after drug administration were statistically greater with tiotropium than with salmeterol, being 83 and 77 mL, respectively (both p < 0.001), in one study, 21 and stated as statistically significant (p < 0.05) in the other study, 22 although numerical values were not provided. The results of these large long-term trials therefore indicate that tiotropium administered once daily raises the trough FEV1 by 0.1 to 0.15 L, and raises the peak FEV1 by a further 0.15 to 0.2 L. In both respects, tiotropium is statistically superior to either ipratropium administered four times daily or salmeterol administered twice daily. No loss of efficacy(tachyphylaxis) was seen over the course of 1 year of regular treatment with tiotropium. Static Lung Volumes and Other Physiologic Effects Airways obstruction, particularly in COPD, is typically accompanied by hyperinflation as signified by an increase in static lung volumes. In COPD, dyspnea correlates more closely with hyperinflation than with FEV1. 24, 25 Conversely, effective bronchodilation and reduction of dyspnea in COPD are typically associated with a reduction in lung volumes. 26 A parameter of lung volumes that is of special interest in COPD is the inspiratory capacity (IC), as it can be measured by spirometry and its increase reflects a decrease in hyperinflation. 24, 27 Two studies have examined the effect of tiotropium on lung volumes including IC. 28, 29 Celli et al 28 reported the effects of 4 weeks of treatment with tiotropium or placebo in patients with COPD. The results show that, in patients who received tiotropium, functional residual capacity was substantially reduced and IC was accordingly increased, indicating a reduction in hyperinflation. 28 These changes in resting lung volumes could be expected to result in an improvement in dyspnea. In a double blind, controlled, clinical trial of tiotropium in 187 patients with COPD, O’Donnell et al 29 found that the reduction in hyperinflation resulted in increases in tidal volume during constant work-rate cycle ergometry, with improvements in endurance time and dyspnea index. Endurance time improved by approximately 21% after 6 weeks of treatment. Other studies of the effects of tiotropium on static lung volumes have not been published to my knowledge, nor have studies on recoil pressures or diffusion capacity. 5 The acute effects of tiotropium on arterial blood gases have been compared with those of salmeterol after 4 weeks of regular therapy with each agent. 30 The results indicate that tiotropium had less tendency (although not statistically significant) to produce transient lowering of the PaO 2 and an increase in the alveolar-arterial P O 2 gradient than salmeterol, consistent with previous studies 31, 32 comparing ipratropium with β-adrenergic agents. Symptom Outcomes Dyspnea: The effect of tiotropium on this cardinal symptom of COPD has been measured by the transition dyspnea index (TDI) of Mahler et al. 33 This questionnaire-based index measures changes in perceived breathlessness from one time to another. Its scale is from -9 (worse) to +9 (better); a change of 1 U is considered to be clinically significant. 34,35 TDI has been systematically measured in all the long-term studies 19–22 already mentioned. The improvement in TDI of tiotropium subjects was statistically significant as compared to placebo, 19, 21, 22 tending to increase with duration of use, and sometimes exceeding the 1-U threshold of clinical significance. 19 In the studies where salmeterol was included, the improvement in TDI with tiotropium was statistically greater than that with salmeterol in one study 21 (p < 0.05), but did not reach statistical significance in the other study. 22 Other Symptoms: In the placebo-controlled study, 19 COPD symptoms (wheezing, shortness of breath, coughing, and chest tightness) were evaluated using a severity score (from 0 to 3) at baseline and at each visit. Wheezing and shortness of breath were significantly improved in the tiotropium group compared with the placebo group (p < 0.05), but not cough or chest tightness. Health Status (Quality of Life) The effects of tiotropium on health status have been measured in each of the long-term studies 19–22 using the St. George’s Respiratory Questionnaire (SGRQ). 36, 37 The total score range is 0 to 100, with lower scores signifying better health status. A difference of 4 U is considered to be clinically significant. It has been validated in patients with COPD. 37, 38 The mean total SGRQ score of subjects who received tiotropium improved significantly compared to baseline in each of these studies, as well as in comparison to placebo 19, 21, 22 or ipratropium, 20 but not compared to salmeterol 21, 22. The proportion of patients who obtained a clinically significant improvement in SGRQ score was likewise greater with tiotropium than with placebo or active control. The improvement with tiotropium occurred at the earliest observation point, and tended either to improve further or to remain constant throughout the trials (p < 0.05). The Medical Outcomes Study Short Form-36 is a generic health status instrument 39 with a number of domains not specific for respiratory disease that has also been used in the 1-year tiotropium 6 trials.19, 20 In both trials, 19, 20 the domains of role physical and physical health summary scores were significantly improved in the tiotropium group in comparison to the control groups (p < 0.05). Acute Exacerbations of COPD Acute exacerbations occur one to three times per year in patients with moderate-to-severe COPD. Each exacerbation is associated with significant mortality and deterioration in lung function and quality of life. 40–42 Exacerbations also account for the major portion of the annual cost of the disease.43 A reduction in the frequency and severity of acute exacerbations is thus an important goal in the management of COPD.3 The effect of tiotropium treatment on the incidence of acute exacerbations has been determined (as a secondary outcome) in each of the long-term studies. 19, 20, 22 The number of COPD exacerbations and hospitalizations due to exacerbations during the treatment period are summarized. Patients receiving tiotropium consistently experienced 20 to 30% fewer exacerbations and hospitalizations than patients in the placebo or ipratropium study arms (p < 0.05). The differences between tiotropium and salmeterol were not statistically significant. A preliminary report of a recent multicenter study 44 in which the time to first exacerbation was the primary outcome showed a statistically significant benefit for patients receiving tiotropium vs the placebo group (p < 0.05). Acute exacerbations of COPD were also less frequent, less likely to require hospitalization, and there was less utilization of health care in patients who were assigned to regular tiotropium, each outcome being less by approximately 20% (p < 0.01). Other Outcomes Other outcomes of major importance include mortality and the long-term rate of decline in lung function. Data on these outcomes are lacking at present, but may be provided by ongoing trials. Safety and Side Effects Tiotropium, like ipratropium, is poorly absorbed from the GI tract and has very low systemic bioavailability. It therefore has a wide therapeutic margin. The most common adverse effect in trials 19–22 has been dryness of the mouth, a typical anticholinergic effect. This was significantly more frequent than in the placebo study arms, and occurred in approximately 10 to 16% of study patients overall, a frequency that may be slightly greater than that observed with ipratropium.19–22 This effect was reported to be mild and rarely led to cessation of the drug. Other adverse events, including serious adverse events, had about the same frequency as in the control groups. Withdrawals from the trials for any reason tended to be less common in the tiotropium groups than 7 the control groups. Bioavailability/pharmacokinetics Absorption If tiotropium is administered by inhalation, about 19.5% will reach the lung. The maximum tiotropium plasma concentration will be observed five minutes after inhalation. For oral solutions, the absolute bioavailability is 2-3%. Besides, tiotropium is poorly absorbed from the gastrointestinal tract because it is a quaternary ammonium compound. Its absorption is also affected by food because of the same reason. Distribution When measured 5 minutes after inhalation of dry powder of a dose of 18 mcg, the peak plasma levels of tiotropium at steady state in COPD patients were 17-19 pg/mL. The plasma level decreases rapidly in a multi-compartmental manner. The steady state trough plasma concentrations were 3-4 pg/mL. However, the local concentration in lung is not known. Furthermore, about 72% of tiotropium is bound by protein and also binds extensively to tissues. It shows a volume of distribution of 32L/Kg. Metabolism The extent of biotransformation appears to be small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, neither of which bind to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase II metabolites. This enzymatic pathway can be inhibited by CYP450 2D6 and 3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. Thus, CYP450 2D6 and 3A4 are involved in the metabolic pathway that is responsible for the elimination of a small part of the administered dose. In vitro studies using human liver microsomes showed that tiotropium in supra-therapeutic concentrations does not inhibit CYP450 1A1, 1A2, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4. 8 Elimination The terminal elimination half- life of tiotropium is between 5 and 6 days following inhalation. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers with an inter-individual variability of 22%. 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. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached after 2–3 weeks with no accumulation thereafter. Dosage forms Inhalation powder, hard capsule It is delivered as a dry powder via a novel single-dose device called Handihaler whose clinical use has been described. Dosage range 10 to 80 ug. The common dosage is 18 ug qd Known Adverse Effect: The most common adverse effect has been dryness of the mouth, a typical anticholinergic effect. Other side effects include nausea, constipation, headache, pharyngitis, sinusitis, candidiasis; rarely tachycardia, difficulty in micturition (urinary retention reported in elderly men with prostatic hyperplasia) Special precautions Tiotropium is best used on a regular daily basis. For the same reason, and also because its peak effect may take some hours to be achieved, tiotropium is not recommended (or approved) for the rapid relief of dyspnea. The approved dose of tiotropium, 18 ug qd, preferably administered in the morning, is optimal and should not be exceeded. It is recommended, rather, that when patients receiving tiotropium experience "breakthrough" dyspnea, they should take a rapidly acting beta2-agonist. Tiotropium in its present dry-powder formulation is not intended or suitable for use with mechanical ventilation. Contraindications: Glaucoma, prostatic hyperplasia and bladder outflow obstruction, pregnancy, and breast-feeding, 9 renal impairement Drug interactions Similar to other quaternary ammonium compounds, systemic absorption of tiotropium is minimal. This makes the likelihood of drug interactions very small. Currently no formal drug interaction studies have been performed. Spiriva inhalation powder has been used concomitantly with other drugs without adverse drug reactions. These include sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids, commonly used in the treatment of COPD. Tiotropium is well tolerated, with little potential for drug interactions. However, the co-administration of tiotropium with other anticholinergic-containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC 0–4h , a 28% decrease in the renal clearance of tiotropium and no significant change in the C max and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium. Therefore, no clinically significant interaction occurred between tiotropium and cimetidine or ranitidine. No interaction study is conducted with inhaled tiotropium. More clinical trials are required to establish and confirm evidence-based interactions between inhaled tiotropium and other medications. However there are some potential drug intereactions due to antimuscarinic effects of tiotropium. They include other antimuscarinics used by inhalation, Amantadine, Antidepressants, Tricyclic Antidepressants, Tricyclic (related) Antihistamines, Clozapine, Disopyramide, Domperidone, Haloperidol, Ketoconazole, Levodopa, MAOIs, Memantine, Metoclopramide, Nefopam, Nitrates, Parasympathomimetics, Phenothiazines Drug/Laboratory Test Interactions In a multicenter, randomized, double-blind trial that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30-60 msec was higher in the tiotropium group as compared with placebo. No patients in either group had either QTcB or QTcF of >500 msec. However other clinical studies with tiotropium did not detect an effect of the drug on QTc intervals. It is controversial to state whether tiotropium has any effect on QT intervial. Patient monitoring guidelines Monitor patient for objective evidence of effectiveness. For instance, observe the patient whether he complain of any episodes of wheezing, shortness of breath, coughing, and chest tightness. Obtain 10 the oxygen saturation and arterial blood gas and normal chemistry values, and monitor regularly. Monitor the adverse effects closely. Patient information Inform the patient that SPIRIVA HandiHaler is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems, which is not used as a rescue medication. It is important for patients to understand how to correctly administer SPIRIVA capsules and using the HandiHaler inhalation device. The capsules should only be administered via the HandiHaler device and the HandiHaler. The device should not be used for administering other medications. Capsules should always be stored in sealed blisters and only removed immediately before use. The blister strip should be carefully opened to expose only one capsule at a time. Open the blister foil as far as the STOP line to remove only one capsule at a time. The drug should be used immediately after the packaging over an individual capsule is opened, or else its effectiveness may be reduced. Capsules that are inadvertently exposed to air, which is not intended for immediate use should be discarded. If the patient experiences any eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema, which may be signs of acute narrow-angle glaucoma, he should consult a physician immediately. Care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation. The following patients should inform their doctors before using SPIRIVA HandiHaler: − pregnant or wish to become pregnant; − breast-feeding mother; − taking any medications including eye drops including those can be bought without a prescription; − having any other medical problems such as difficulty urinating or an enlarged prostate; − allergic to any medications. Use this product as directed, unless instructed to do otherwise by physician. Pharmacoeconomic analysis Exacerbations of COPD and hospitalizations contribute to the major portion of the annual cost of the disease. Thus a reduction in the frequency and severity of acute exacerbations is thus an important goal in the management of COPD. Tiotropium is indicated for the long-term, once-daily, 11 maintenance treatment of bronchospasm associated with COPD. The following trials study Tiotropium in the pharmacoeconomic point of view: 1. One-year cost-effectiveness of tiotropium versus ipratropium to treat chronic obstructive pulmonary disease. 45 Problem definition: The objective was to compare the cost-effectiveness of tiotropium and ipratropium in the management of COPD. The study was conducted in the Netherlands and Belgium. Perspective: In was on the side of the country. Specific treatment alternatives and outcomes: The two dugs are compared in terms of improvement in health outcomes, exacerbation rate and rate of hospitalization. Pharmacoeconomic model: A cost-effectiveness analysis was performed. There was a greater improvement in health outcomes with tiotropium. The exacerbation rate was lower with tiotropium.However, the rate of hospitalization due to exacerbation was not significantly different between the groups. The costs includes the inpatients days, unscheduled visits, medications, diagnostic or prognostic tests, and ambulance transport. The overall health care costs for 1 year were 180€ greater for tiotropium than ipratropium and was mainly due to the cost of tiotropium. Therefore, the use of tiotropium instead of ipratropium provides a improved health outcomes at an increased cost of 180€ per patient year. The cost of tiotropium and other bronchodilators used to treat COPD is listed in the following table: 12 2. A comparison of the costs and effects of bronchodilator therapies for the treatment of patients with COPD. 46 Problem Definition: The study compares the three bronchodilators: tiotropium (an anticholinergic for once-daily dosing), ipratropium (an anticholinergic for four times daily dosing) and salmeterol (a beta-agonist for twice-daily dosing) in the Netherlands and Canada. Pharmacoeconomic model: Model inputs about the effectiveness of treatments were derived from the clinical trial program of tiotropium. The model showed that the mean number of exacerbations per patient per year ranged from 0.85 in the tiotropium group, to 1.02 in the salmeterol group and to 1.14 in the ipratropium group. The difference between tiotropium and ipratropium was statistically significant (p<0.05). In the Netherlands, 1-year health care costs in the tiotropium and salmeterol groups were approximately 150€ lower than in the ipratropium group. In Canada, costs were about the same in all treatment groups. And so tiotropium is associated with a reduction in the number of exacerbations without increasing health care costs. 3. Healthcare Costs with Tiotropium Plus Usual Care versus Usual Care Alone Following 1 Year of Treatment in Patients with Chronic Obstructive Pulmonary Disorder (COPD) 47 Problem Definition: The objective is to compare the healthcare Costs with Tiotropium Plus Usual Care versus Usual Care Alone Following 1 Year of Treatment in Patients with COPD. Perspective: It was in terms of the US healthcare setting. Specific alternatives and outcomes: Tiotropium plus usual care and usual care are compared. Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting -adrenoceptor agonists. Pharmacoeconomic model: The cost of the treatment was measured. Medical care resource utilisation was recorded at every scheduled visit in each trial. Mean total costs were calculated retrospectively.Resource utilisation and clinical data were prospectively collected for the two 1-year, randomised, double-blind trials of tiotropium plus usual care versus usual care alone (placebo) in 13 921 patients with COPD. Compared with usual care, patients receiving tiotropium had significantly fewer COPD exacerbations (20% decrease), hospitalisations (44% reduction) and hospital days (50% reduction). And so patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone (tiotropium $US1738 ± $US259; placebo $US2793 ± $US453). The cost of hospital admissions accounted for 48% of the total direct medical costs in this trial. Thus Tiotropium can reduced the overall cost of hospitalization. Therefore, tiotropium can reduce the frequency of exacerbation and hospitalization in COPD. And can significantly lower the mean per- patient costs of hospitalisation. Summary: Tiotropium is an inhaled, once-daily anticholinergic bronchodilator that has been used in the maintenance treatment of chronic obstructive pulmonary disease. It is closely related to ipratropium but its duration of action is much longer. So it offers the convenience of once daily dosing. Majority of the clinical studies demonstrated that it is superior or comparable to ipratropium and the long-acting beta-agonists in terms of treatment outcomes. Nevertheless, some studies also showed that it causes slightly more side effects than ipratropium, with dry mouth being the most common. Only about 25% of tiotropium is metabolized by CYP450 enzymes. Majority is excreted unchanged in urine. It is available in dry powder and hard capsule form, using handihaler to administer. The common dosage is 18 ug per day. Up to now no formal drug interaction in associated with tiotropium has been confirmed. Although the acquisition cost of tiotropium considerably exceeds that of ipratropium and the long-acting beta-agonists, some pharmacoeconomic studies showed that tiotropium is associated with a reduction in the number of exacerbations without increasing health care or hospitalization costs. 14 References: 1. Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. 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