Tiotropium bromide is a quaternary ammonium derivative long-acting muscarinic antagonist (LAMA) that is administered once daily. Tiotropium is indicated in adults for the maintenance treatment of chronic obstructive pulmonary disease (COPD) and is also FDA-approved for asthma maintenance treatment in adult and pediatric patients 6 years and older. For patients with COPD, tiotropium's effects on trough and peak FEV1 and trough FVC are sustained with continued use and may lead to a reduction in the use of short-acting beta-agonists; data from a 6-month study indicate significant improvement in bronchodilation, dyspnea, and health-related quality of life scores (HRQoL). A 4-year, randomized, multicenter, double-blind, parallel-group, placebo-controlled trial (Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT)) was conducted; tiotropium was associated with a reduction in the risks of COPD exacerbations, related hospitalizations, and respiratory failure. According to guidelines, LAMAs may be used as initial monotherapy in COPD patients in group A. A long-acting bronchodilator is the preferred choice except in patients with very occasional breathlessness. In patients with stable disease, LAMAs have a greater effect on exacerbation reduction compared to long-acting beta-agonists (LABAs) and decrease hospitalizations. In patients in Group B and Group E, LAMAs are used as initial therapy in combination with LABAs. At follow-up, if the patient is still experiencing dyspnea, consider switching inhaler device, implement or escalate non-pharmacologic treatment(s), and investigate for other causes of dyspnea. If the patient has exacerbations, consider triple therapy with a LAMA, a LABA, and an inhaled corticosteroid (ICS). GINA states that tiotropium inhalation may be used as add-on therapy to an ICS-LABA regimen in adult and pediatric patients 6 years and older with moderate-to-severe asthma and a history of asthma exacerbation; per GINA there is insufficient evidence to recommend use of a LAMA in place of a LABA in combination with ICS. The addition of tiotropium produces small but statistically significant improvements in FEV1 and modestly reduces the risk of severe asthma exacerbation in patients with poorly controlled asthma who are already receiving high-dose ICS and LABAs. The NAEPP guidelines conditionally recommend adding LAMA as add-on therapy in patients 12 years and older who have uncontrolled persistent asthma despite use of an ICS-LABA controller regimen; in general, an ICS-LAMA regimen is not recommended in place of an ICS-LABA regimen in these patients with persistent asthma unless LABA cannot be used. The NAEPP did not examine the role of LAMA treatment in asthmatic children 6 to 11 years of age.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Inhalation Administration
Oral Inhalation Administration
-For inhalation use only.
-Administer at the same time each day.
Inhalation Powder (Spiriva HandiHaler):
-Instruct patients NOT to swallow the capsules; cases of inadvertent oral administration have been reported to the FDA.
-The dry-powder capsule inhaler (HandiHaler) delivers drug at inspiratory rates as low as 20 L/minute. Patients with severe COPD (FEV1 <= 27% of predicted) have demonstrated successful use of the HandiHaler.
-Open and prepare mouthpiece of HandiHaler according to package instructions.
-Load the oral inhaler with an inhalation capsule immediately prior to use (see package insert). Discard any capsule that is exposed to air (opened and not used immediately). Place a single capsule in the device. Press the button to puncture the capsule.
-To inhale a dose: Hold the mouthpiece level to, but away from, the mouth, and exhale fully. Then, put the mouthpiece to the mouth, tightly close lips, and breathe in the dose deeply and slowly; inhale so as to hear or feel the capsule vibrate within the inhaler. Remove the HandiHaler from the mouth, hold breath for at least 10 seconds, and then exhale slowly away from the inhaler. To ensure full dose delivery, repeat deep exhale and slow inhale from HandiHaler a second time. Do not press the button to puncture the capsule a second time.
-If the capsule does not vibrate during inhalation of the medicine, gently tap the inhaler on a table while holding it in an upright position. Verify that the mouthpiece is closed properly and repeat administration. Do not press the button to pierce the capsule again. Advise patients to contact their health care professional to review correct administration technique if the capsule still does not vibrate while inhaling.
-Occasionally the gelatin capsule might break into very small pieces which pass through the inhaler screen and reach the mouth or throat. Advise patients that this is normal and not expected to cause harm.
-After administration, instruct patient to dispose of the used capsule prior to storing the inhaler and to rinse mouth with water to minimize dry mouth.
-To avoid the spread of infection, do not use the HandiHaler device for more than one person.
-The HandiHaler may be rinsed with warm water and air dried as needed, according to package instructions. Do not use the inhaler device when it is wet.
Inhalation spray (Spiriva Respimat):
-Instruct patient on proper inhalation technique according to product directions.
-Prior to first use, insert the cartridge into the inhaler and prime the unit by actuating the inhaler toward the ground until an aerosol cloud is visible and then repeating the process 3 more times. The unit is then considered primed and ready for use. Do not remove the cartridge once it has been inserted into the inhaler. If the inhaler is not used for more than 3 days, actuate the inhaler once to prepare the inhaler for use. If not used for more than 21 days, actuate the inhaler until an aerosol cloud is visible and then repeat the process 3 more times to prepare the inhaler for use.
-To inhale a dose: Hold the inhaler upright with the cap closed, so as to not accidentally release a dose of medicine. Turn the clear base in the direction of the arrows on the label until it clicks (half a turn). Then, flip the cap until it snaps fully open. Have patient breathe out slowly and fully, and then close their lips around the end of the mouthpiece without covering the air vents. Point the inhaler to the back of the throat. While the patient takes in a slow, deep breath through the mouth, press the dose release button and continue to have the patient breathe in slowly for as long as the patient can. The patient should hold the breath for 10 seconds or for as long as comfortable. These steps should be repeated twice to receive the proper dose of medicine. After the second inhalation, close the cap until it is time to use the inhaler again.
-The mouthpiece, including the metal part inside the mouthpiece, should be cleaned with a damp cloth or tissue only, at least 1 time a week; any minor discoloration in the mouthpiece does not affect the inhaler. If the outside of the inhaler gets dirty, wipe it with a damp cloth.
-The inhaler contains either 60 puffs (equal to 30 doses of medicine) or 28 puffs (equal to 14 doses of medicine) after prepared for the first use. The dose indicator shows approximately how much medicine is left. When the pointer enters the red area of the scale, there is enough medicine for 7 days (30 dose product) or 3 days (14 dose product); once the dose indicator has reached the end of the scale, all puffs have been used and the inhaler locks automatically. At this point, the base cannot be turned any further.
-The inhaler should be discarded 3 months after insertion of cartridge into inhaler, even if all the medicine has not been used, or when the inhaler is locked, whichever comes first.
In March 2008, the FDA and the manufacturer alerted health care professionals of a possible increased risk for stroke based on the pooled analysis of safety data from 29 placebo controlled studies. Since these initial communications, FDA has completed its analysis of the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial. UPLIFT was a large, 4-year clinical trial that compared tiotropium to placebo in 5,992 patients with COPD. In the UPLIFT trial, there was no significant increase in the risk of stroke [0.95 (95% CI 0.70, 1.29)], heart attack [0.73 (95% CI 0.53, 1.00)], or cardiovascular death [0.73 (95% CI 0.56, 0.96)] between tiotropium and placebo. In November 2009, the FDA Pulmonary - Allergy Drugs Advisory Committee also reviewed data from the UPLIFT trial and voted that the findings adequately resolve the potential safety concerns for stroke, heart attack and cardiovascular death. FDA has now completed its review and believes the available data do not support an association between the use of tiotropium and an increased risk for these serious adverse events.
The most common gastrointestinal (GI) effect associated with tiotropium is mild xerostomia (4.1 to 16% of patients). Xerostomia was often mild and often resolved during treatment. Constipation was reported in 1 to 5.1% of patients and may be related to anticholinergic effects. The incidence of xerostomia and constipation increased with age during the 1 year trials. Other GI effects, such as vomiting (1 to 4%), dyspepsia (1 to 6%), abdominal pain (0.5 to 6%), gastrointestinal disorder not otherwise specified (1 to 3%), gastroesophageal reflux (0.5 to 3%), stomatitis (including ulcerative stomatitis) (1 to 3%), and diarrhea (1 to 2%) were also reported. In the clinical trials with tiotropium inhalation spray, oropharyngeal discomfort, dysphagia, gingivitis, and GI obstruction (including paralytic ileus) occurred with an incidence of < 1% and at a higher incidence rate than with placebo. Post-marketing reports indicate that gastrointestinal-related effects have occurred including dysphagia, hoarseness, GI obstruction (including paralytic ileus), and throat irritation. Application site irritation noted during post-marketing reports included glossitis, oral ulceration, and pharyngolaryngeal pain.
Tiotropium has been reported to cause clinically significant cardiovascular effects in some patients, but these are infrequent or rare. During asthma trials in adult and pediatric patients, hypertension (1% to 2%) was reported at a rate greater than placebo. Chest pain (unspecified) and palpitations have been reported in 0.5% to less than 1% of adult and pediatric patients with asthma receiving tiotropium inhaler 2.5 mg/dose; COPD patients receiving 5 mg/dose reported palpitations at an incidence of 1% to 3%. During postmarketing experience, atrial fibrillation, sinus tachycardia, and supraventricular tachycardia (SVT) have been reported.
Central nervous system (CNS) adverse effects reported in tiotropium trials include dysphonia (0.5 to 3%), paresthesias (1 to 3%), depression (1 to 4.4%), insomnia (0.5 to 4.4%), and headache (3.8 to 5.7%). Dizziness was reported in 1 to 3% of patients receiving tiotropium inhalation spray, and at a higher incidence than patients on placebo.
Tiotropium may increase intraocular pressure and aqueous outflow resistance and may precipitate or exacerbate ocular hypertension or closed-angle glaucoma. Glaucoma, increased intraocular pressure, and blurred vision have occurred during postmarketing experience with tiotropium. Advise patients to promptly report new-onset signs and symptoms of glaucoma including ocular pain or discomfort, blurred vision, visual impairment with halos or colored images in association with red eyes from conjunctival congestion and corneal edema. Since dizziness and blurred vision may occur, warn patients about engaging in activities such as driving and operating machinery. Cataracts have been reported in 1-3% of patients in trials. Temporary ocular irritation, ocular pain, mydriasis, cycloplegia, blurred vision, conjunctivitis, or visual impairment may result from inadvertent ocular exposure of tiotropium powder.
Urinary retention due to anticholinergic effects, although unlikely, might occur if significant amounts of tiotropium are absorbed systemically. Advise patients to promptly report new-onset signs and symptoms of prostatic hypertrophy or bladder neck obstruction including urinary retention or urethral pain/painful urination/dysuria. Urinary retention and dysuria were reported in < 1% of patients receiving tiotropium inhalation spray, and at a higher incidence than patients on placebo. Use tiotropium cautiously in patients with pre-existing prostatic hypertrophy or other urinary tract disorders.
Allergic reactions to tiotropium have been reported in 0.5 to 3% of tiotropium patients in trials. Anaphylactoid reactions, angioedema (swelling of the lips, tongue, or throat), pruritus, and rash may occur with tiotropium. In hypersensitive patients, anaphylactic shock may be possible. Angioedema has been reported in < 2% of patients during trials. Pruritis was reported in 1 to 3% of patients receiving tiotropium inhalation spray, and at a higher incidence than patients on placebo. Anaphylactoid reactions with ipratropium, another anticholinergic bronchodilator, have manifested as urticaria, angioedema of the tongue, lips, and face, maculopapular rash, laryngospasm, pruritus, and laryngeal edema. Post-marketing reports indicate that hypersensitivity (including immediate reactions) and urticaria have occurred with tiotropium administration, although the exact incidence has not been established.
Tiotropium may cause paradoxical bronchospasm. If this occurs, treat immediately with an inhaled short-acting beta-2 agonist, discontinue tiotropium, and consider other treatment options. In COPD clinical trials with tiotropium inhalation spray, COPD exacerbation was the adverse event most commonly leading to discontinuation of therapy (2% vs. 4% placebo) and was also the most frequent serious adverse event. Other respiratory adverse events that have been reported in COPD and/or asthma clinical trials include bronchitis (3.3%), sinusitis (2.7 to 11%), pharyngitis (7 to 15.9%), rhinitis (0.5 to 6%), epistaxis (< 4%), laryngitis (< 3%), and tonsillitis (< 1%). In COPD clinical trials, cough was reported in 5.8% of patients receiving tiotropium inhalation spray vs. 5.5% of patients on placebo. In asthma trials, cough occurred in 1 to 2% of patients and at a higher rate than placebo.
Musculoskeletal adverse events reported in tiotropium clinical trials include myalgia (4%), leg pain (1 to 3%), musculoskeletal pain (1 to 3%), arthralgia (0.5 to 4.2%), joint swelling (< 1%), muscle spasms (< 1%), pain in extremity (< 1%).
General infection was reported in 1 to 4% of patients during tiotropium trials. Specific infectious processes reported include candidiasis (3 to 4%), upper respiratory tract infection (41 to 43%), herpes zoster (0.5 to 3%), urinary tract infection (1 to 7%), and skin infection (< 1%). An increased incidence of urinary tract infections was noted with increased adult age during 1 year trials. Oropharyngeal candidiasis (1 to 3%) and fever (1 to 2%) were reported in patients receiving tiotropium inhalation spray, and at a higher incidence than patients on placebo.
Rash (unspecified) has been reported in 1-4% of patients during tiotropium clinical trials. Additionally skin ulcer and dry skin (xerosis) have been reported in < 1% of patients receiving tiotropium inhalation spray, and at a higher incidence than patients on placebo.
Dependent peripheral edema was reported in 3 to 5% of patients during tiotropium trials. Dehydration was also reported more with tiotropium in clinical trials than with placebo.
Elevated hepatic enzymes and abnormal liver function tests were reported in 1 to 2% of patients during tiotropium clinical trials. Hypercholesterolemia and hyperglycemia were both reported in 1 to 3% of patients during tiotropium clinical trials.
Carefully instruct patients on appropriate use of the Spiriva HandiHaler; there have been reports of patients swallowing the capsules, rather than placing the capsule in the inhaler-device for administration.
Tiotropium capsules for inhalation (Spiriva HandiHaler) contain lactose as a carrier; the lactose may contain milk proteins. Caution should be exercised in patients with a true lactose hypersensitivity. Gastrointestinal lactose intolerance is not usually evident until greater than 3 grams of lactose has been consumed, and should not be a concern with the use of inhaled tiotropium. However, patients with a severe milk protein hypersensitivity may experience an allergic reaction to the product. Tiotropium inhalation spray (Spiriva Respimat) does not contain lactose and does not contain a warning for patients with lactose or milk protein hypersensitivity.
Tiotropium is not intended for rescue therapy of acute COPD- or asthma-related bronchospasm attacks. Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after administration. If such a reaction occurs, stop the therapy at once and consider alternative treatments. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to the inhalation. Inhaled medicines, including tiotropium inhalation, can produce paradoxical acute bronchospasm. If acute bronchospasm occurs during use with tiotropium, the drug should be discontinued and appropriate treatment measures instituted.
All anticholinergics should be used with caution in patients with closed-angle glaucoma. Significant systemic absorption, while unlikely with tiotropium, may aggravate this condition. Tiotropium may increase intraocular pressure and aqueous outflow resistance in patients with closed-angle glaucoma, particularly if the medication gets into the eyes (i.e., inadvertent ocular exposure). Temporary pain, mydriasis, cycloplegia, blurred vision, conjunctivitis, or visual impairment may result from inadvertent ophthalmic administration. Care should be taken not to get tiotropium powder in the eyes. The anticholinergic effects of tiotropium may make the eyes dry and this can cause irritation or blurred vision for wearers of contact lenses. The use of lubricating drops may be necessary.
Anticholinergics should be used with caution in patients with preexisting bladder obstruction (of the bladder neck) or other urinary tract obstruction, or in patients with prostatic hypertrophy. Tiotropium may precipitate urinary retention in patients with these conditions. Although inhaled tiotropium is only minimally absorbed into the systemic circulation, the effects of tiotropium may be additive to other concomitantly administered anticholinergic medications.
Chest pain has been infrequently noted in some studies with tiotropium but causality has not been established. Significant changes in ECG, heart rate or blood pressure did not occur in clinical trials. However, postmarketing reports indicate that palpitations and tachycardia are possible with tiotropium administration. Clinicians should use caution in administering tiotropium to patients with a risk for cardiac arrhythmias until further data are available.
Because tiotropium is predominantly eliminated in the urine, patients with moderate to severe renal impairment (CrCl < 60 mL/minute) may be at an increased risk of anticholinergic-induced events. Although an increase in monitoring may be needed in such patients, dosage adjustments are generally not required.
Tiotropium may cause dizziness and blurred vision, therefore caution patients about driving or operating machinery until they are aware of how the medication affects them.
Any anticholinergic drug should be used with caution in geriatric patients, due to their greater sensitivity to anticholinergic effects. Although tiotropium has minimal systemic absorption, additive effects may occur in geriatric patients receiving several anticholinergic medications concurrently. The geriatric patient should also be warned of the risk for blurred vision or dizziness. Any hazardous tasks, including driving, should be avoided until the geriatric patient knows how the drug might affect them. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). The OBRA guidelines caution that inhaled anticholinergic drugs, such as tiotropium, can cause xerostomia.
There are no adequate and well controlled studies of tiotropium in pregnant women. The limited data with tiotropium during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. No structural abnormalities were observed during animal reproduction studies in pregnant rats and rabbits, however, increased post-implantation loss was observed when tiotropium was administered at maternally toxic doses. Tiotropium should only be used during pregnancy if the potential benefit to the mother outweighs any potential risks to the fetus. The safety and effectiveness of tiotropium has not been studied during labor and delivery.
There is no data on the presence of tiotropium in human milk, the effects on the breast-feeding infant, or the effects on milk production. Tiotropium is present in lactating rats; however, it is not known whether tiotropium is excreted in human breast-milk. However, because of low systemic concentrations in the mother and poor absorption from the gastrointestinal tract (i.e. 2% to 3%), it is unlikely that maternal use of tiotropium would result in clinically significant exposure to a breast-feeding infant. As with all medications, if the drug is used in a breast-feeding mother, the infant should be monitored for possible adverse effects. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Safety and effectiveness of tiotropium have not been established in children and infants under 6 years of age.
For asthma maintenance treatment:
Respiratory (Inhalation) dosage (inhalation spray; e.g., Spiriva Respimat):
Adults: 2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily. It may take up to 4 to 8 weeks of therapy to see the maximum benefit in lung function in asthmatic patients.
Children and Adolescents 6 to 17 years: 2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily. It may take up to 4 to 8 weeks of therapy to see the maximum benefit in lung function in asthmatic patients.
Children 1 to 5 years*: Efficacy has not been established; safety has been studied. 2.5 mcg (2 actuations of 1.25 mcg/actuation) inhaled by mouth once daily was delivered with the AeroChamber Plus Flow-Vu valved holding chamber with facemask. The adverse reaction profile in the treated group (mean age: 3.1 years) was similar to that observed in adult and older pediatric patients.
For the maintenance treatment of chronic obstructive pulmonary disease (COPD), (e.g., chronic bronchitis or emphysema) and to reduce exacerbations of COPD:
Oral Inhalation dosage (inhalation spray; e.g., Spiriva Respimat):
Adults: 2 actuations (2.5 mcg/actuation) via oral inhalation once daily (total daily dose: 5 mcg) at the same time each day, is the usual and max dosage. Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently. According to guidelines, tiotropium and other LAMAs may be used as initial monotherapy in COPD patients in group A. A long-acting bronchodilator is the preferred choice except in patients with very occasional breathlessness. In patients with stable disease, LAMAs have a greater effect on exacerbation reduction compared to long-acting beta-agonists (LABAs) and decrease hospitalizations. In patients in Group B and Group E, LAMAs are used as initial therapy in combination with LABAs. At follow-up, if the patient is still experiencing dyspnea, consider switching inhaler device, implement or escalate non-pharmacologic treatment(s), and investigate for other causes of dyspnea. If the patient has exacerbations, consider triple therapy with a LAMA, a LABA, and an inhaled corticosteroid (ICS). In clinical trials, tiotropium improved COPD symptoms, improved general health status, and reduced exacerbation rates and hospitalizations. Dyspnea, as a secondary endpoint, has been shown to be improved.
Oral Inhalation dosage (powder capsule for inhalation; e.g., Spiriva HandiHaler):
Adults: 2 oral inhalations of the contents of a single capsule (18 mcg) once daily using the Handihaler device at the same time each day. Max: 18 mcg/24 hours (contents of 1 inhalation capsule). Not indicated for the relief of acute bronchospasm. Use an inhaled short-acting beta-2 agonist (SABA) for immediate relief of acute symptoms. Do not use other long-acting muscarinic antagonists (LAMAs) concurrently. According to guidelines, tiotropium and other LAMAs may be used as initial monotherapy in COPD patients in group A. A long-acting bronchodilator is the preferred choice except in patients with very occasional breathlessness. In patients with stable disease, LAMAs have a greater effect on exacerbation reduction compared to long-acting beta-agonists (LABAs) and decrease hospitalizations. In patients in Group B and Group E, LAMAs are used as initial therapy in combination with LABAs. At follow-up, if the patient is still experiencing dyspnea, consider switching inhaler device, implement or escalate non-pharmacologic treatment(s), and investigate for other causes of dyspnea. If the patient has exacerbations, consider triple therapy with a LAMA, a LABA, and an inhaled corticosteroid (ICS). In clinical trials, tiotropium improved COPD symptoms, improved general health status, and reduced COPD exacerbation rates and hospitalizations. Dyspnea, as a secondary endpoint, has been shown to be improved.
Therapeutic Drug Monitoring:
Patients receiving tiotropium inhalation should have their pulmonary function tests (including FEV1 and FVC) monitored at the beginning of therapy and periodically thereafter to assess for COPD exacerbations. Therapeutically, coughing, tightness in the chest, dyspnea, wheezing and sputum production should improve with the use of tiotropium.
Maximum Dosage Limits:
-Adults
2.5 mcg/day for asthma or 5 mcg/day for COPD for inhalation spray; 18 mcg/day for dry powder inhaler.
-Geriatric
2.5 mcg/day for asthma or 5 mcg/day for COPD for inhalation spray; 18 mcg/day for dry powder inhaler.
-Adolescents
2.5 mcg/day for inhalation spray.
-Children
6 to 12 years: 2.5 mcg/day for inhalation spray.
6 years and younger: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Monitor patients with moderate to severe renal impairment (CrCl < 60 mL/minute) for anticholinergic effects.
*non-FDA-approved indication
Aclidinium: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Aclidinium; Formoterol: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Anticholinergics: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Atropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Atropine; Difenoxin: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Belladonna; Opium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Benztropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Chlordiazepoxide; Clidinium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Dicyclomine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Diphenoxylate; Atropine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Flavoxate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Glycopyrrolate; Formoterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Homatropine; Hydrocodone: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Hyoscyamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Indacaterol; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Methacholine: (Major) Discontinue use of tiotropium 168 hours or more before a methacholine challenge test. Tiotropium inhibits the airway response to methacholine.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Methscopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Neostigmine; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Oxybutynin: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Propantheline: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Trihexyphenidyl: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Tiotropium antagonizes the action of acetylcholine by blocking muscarinic cholinergic receptors. The parasympathetic nervous system has an important role in the automatic control of the airways and is responsible for resting bronchomotor tone. Tiotropium has both bronchodilatory and bronchoprotective actions and is antagonistic at M1, M2, and M3 muscarinic receptors. Each muscarinic receptor serves a unique physiological function. M1 receptors facilitate cholinergic neurotransmission via parasympathetic ganglia. M2 receptors, located on post-ganglionic cholinergic nerves, modulate negative feedback for acetylcholine release. M3 receptors, found on bronchial smooth muscle and mucous glands, are responsible for the airway contraction and mucous secretion in response to acetylcholine. Tiotropium is selective for and dissociates slowly from M1 and M3 receptors (which mediate bronchoconstriction), and dissociates more rapidly from M2 receptors (which inhibit acetylcholine release from cholinergic nerve endings). In the lung, this receptor antagonism and slow dissociation results in bronchodilation and a 24-hour duration of action. The half-lives for release of tiotropium from the M1, M2 and M3 receptors are 14.6, 3.6 and 34.7-hours, respectively. Tiotropium is 10-fold more potent than ipratropium. For all receptor subtypes, tiotropium dissociates more slowly than ipratropium (0.04 to 0.26-hour half-life). Dose-ranging studies have shown that increases in FEV1 are dose-dependent up to a 72 mcg single dose with values remaining above baseline FEV1 for 72 hours.
Tiotropium is administered as a dry-powder via oral inhalation and as an inhalation spray. A pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the inhalation spray (5 mcg inhaled dose) and as inhalation powder (18 mcg inhaled dose) resulted in a similar systemic exposure between the two products. After intravenous dosing, tiotropium is 72% protein bound with a Vd of 32 L/kg; local concentrations in the lung are not known, but expected to be higher with orally inhaled administration. Animal studies have shown tiotropium does not penetrate the blood-brain barrier. In an unpublished study, accumulation of tiotropium did not occur in the plasma or urine once steady-state was achieved. Approximately 7% of the delivered dose (roughly equivalent to 0.25 mcg) appears unchanged in the urine at steady-state. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (25% of an intravenous dose) is metabolized by CYP450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. It appears the drug and its metabolites are mostly excreted renally. In a pharmacokinetic study, 74% of intravenously administered tiotropium was excreted in urine as unchanged drug. After once daily administration of the inhalation spray, the terminal half-life of tiotropium in COPD and asthma patients is 25 and 44 hours, respectively. Terminal elimination half-life is between 5 to 6 days after dry-powder inhalation.
Affected Cytochrome P450 (CYP 450) enzymes and drug transporters: CYP2D6, CYP3A4
In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (25% of an intravenous dose) is metabolized by CYP450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited by CYP2D6 and 3A4 inhibitors. Thus, CYP2D6 and CYP3A4 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.
-Route-Specific Pharmacokinetics
Inhalation Route
After oral inhalation, there is minimal systemic absorption of tiotropium, reducing the chance for systemic side effects. Roughly 20% of a dose is deposited in the lung. The onset of action is within 30 minutes, but duration of action is close to 24 hours allowing once-daily dosing. Peak effects (increase in FEV1 of 19% to 26% greater than baseline) occur in roughly 1 to 4 hours. Peak and trough plasma concentrations are roughly 16 ng/L and 4 ng/L, respectively, although plasma concentrations are not used to monitor clinical response. Peak concentrations are achieved in 5 to 7 minutes, and trough concentrations in less than 60 minutes. Increases in FEV1 are dose-related; trough FEV1 and FVC average greater than 12% over baseline one week after tiotropium administration. After long-term once-daily inhalation, steady state is achieved within 1 week in COPD and asthma patients receiving the inhalation spray and 2 to 3 weeks in COPD patients receiving the dry-powder inhaler. For asthma, maximum bronchodilator effect may take up to 4 to 8 weeks.
-Special Populations
Hepatic Impairment
Pharmacokinetic studies in patients with hepatic impairment have not been undertaken.
Renal Impairment
After 4-weeks of tiotropium inhalation spray 5 mcg once daily dosing in patients with COPD, mild renal impairment (CrCl 60 to 90 mL/minute) resulted in 23% higher AUC and 17% higher Cmax at steady-state and moderate renal impairment (CrCl 30 to 60 mL/minute) resulted in 57% higher AUC and 31% higher Cmax at steady state when compared to COPD patients with normal renal function (CrCl > 90 mL/minute). The influence of mild to moderate renal impairment on systemic exposure in asthmatic patients receiving tiotropium inhalation spray 2.5 mcg once daily is similar. Data in patients with severe renal impairment (CrCl < 30 mL/minute) are insufficient. In one pharmacokinetic study, the AUC and Cmax were 94% and 52% higher, respectively, in patients with severe renal impairment following intravenous infusion of tiotropium compared to healthy adults.
Pediatrics
Tiotropium exposure does not differ between pediatric patients 12 to 17 years of age and adults with asthma.
Geriatric
The pharmacodynamic parameters of tiotropium do not appear to be affected by age. While an age-related decline in renal clearance occurs (347 mL/minute in COPD patients < 65 years and 275 mL/min in COPD patients >= 65 years), the exposure (AUC) and maximal concentrations at steady state (Cmax) do not appear altered with age.
Gender Differences
The pharmacodynamic parameters of tiotropium do not appear to be affected by gender.