STIOLTO RESPIMAT

Respiratory Long-Acting Beta-2 Agonists in Combination with Respiratory Long-Acting Muscarinic Antagonists

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 three more times. The unit is then considered primed and ready for use. 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 three more times to prepare the inhaler for use.
Administration of inhalations: Hold the inhaler upright with the light green cap closed, so as to not accidentally release a dose of medicine. Step A: Turn the clear base in the direction of the black arrows on the label until it clicks (half a turn). Then, flip the light green cap until it snaps fully open. Step B: 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. Repeat these steps (A and B) for the next inhalation, to administer the full dose. Step C: After administering the required number of inhalations, close the light green 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 once per 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.

ileus / Delayed / 0-3.0
GI obstruction / Delayed / 0-3.0
anaphylactoid reactions / Rapid / 0-3.0
angioedema / Rapid / 0-3.0
bronchospasm / Rapid / 0-3.0
atrial fibrillation / Early / Incidence not known
visual impairment / Early / Incidence not known
ocular hypertension / Delayed / Incidence not known
asthma-related death / Delayed / Incidence not known

peripheral edema / Delayed / 3.0-5.0
candidiasis / Delayed / 0-3.0
dysphonia / Delayed / 0-3.0
glossitis / Early / 0-3.0
stomatitis / Delayed / 0-3.0
constipation / Delayed / 0-3.0
dehydration / Delayed / 0-3.0
skin ulcer / Delayed / 0-3.0
dysuria / Early / 0-3.0
urinary retention / Early / 0-3.0
blurred vision / Early / 0-3.0
dysphagia / Delayed / 0-1.0
chest pain (unspecified) / Early / 0.5-0.9
supraventricular tachycardia (SVT) / Early / Incidence not known
QT prolongation / Rapid / Incidence not known
hypertension / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
hypokalemia / Delayed / Incidence not known
palpitations / Early / Incidence not known
depression / Delayed / Incidence not known
wheezing / Rapid / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known

pharyngitis / Delayed / 12.4-12.4
rhinitis / Early / 3.0-6.0
abdominal pain / Early / 5.0-6.0
dyspepsia / Early / 1.0-6.0
headache / Early / 5.7-5.7
insomnia / Early / 4.4-4.4
myalgia / Early / 4.0-4.0
vomiting / Early / 1.0-4.0
cough / Delayed / 3.9-3.9
back pain / Delayed / 3.6-3.6
infection / Delayed / 0-3.0
sinusitis / Delayed / 0-3.0
laryngitis / Delayed / 0-3.0
epistaxis / Delayed / 0-3.0
musculoskeletal pain / Early / 1.0-3.0
arthralgia / Delayed / 0-3.0
xerostomia / Early / 0-3.0
gingivitis / Delayed / 0-3.0
gastroesophageal reflux / Delayed / 0-3.0
urticaria / Rapid / 0-3.0
rash / Early / 0-3.0
xerosis / Delayed / 0-3.0
pruritus / Rapid / 0-3.0
paresthesias / Delayed / 1.0-3.0
dizziness / Early / 0-3.0
fever / Early / 2.0
ocular pain / Early / Incidence not known
ocular irritation / Rapid / Incidence not known

STIOLTO RESPIMAT

Rx

Inhaled long-acting muscarinic antagonist (LAMA), (tiotropium) with a long-acting beta-2 adrenergic agonist (LABA), (olodaterol); used once daily
Used in adults for the maintenance treatment of COPD, including chronic bronchitis and/or emphysema
Not indicated for the relief of acute bronchospasm or for the treatment of asthma

2 oral inhalations (tiotropium 2.5 mcg with olodaterol 2.5 mcg per actuation) once daily, at the same time each day, is the recommended and max dose. 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 beta-agonists (LABAs) or long-acting muscarinic antagonists (LAMAs) concurrently.[59724] According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, tiotropium; olodaterol may be used as initial therapy for patients in group D (those with a high risk of exacerbation). At follow-up, if the patient is still experiencing dyspnea, consider switching inhaler device 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).[63765] Both LAMAs and LABAs reduce the risk of COPD exacerbations. Combination therapy is associated with greater improvements in lung function compared to monotherapy. However, more data are needed to confirm an increased effect on exacerbation rates compared to either component alone.[60933] [60943] [63765]

No dose adjustment is needed in patients with mild and moderate hepatic impairment. A study in subjects with severe hepatic impairment was not performed.

No dosage adjustments are needed in renal impairment. However, patients with moderate to severe renal impairment should be monitored closely for anticholinergic effects of tiotropium; olodaterol.

Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. Agents associated with a lower, but possible risk for QT prolongation and torsade de pointes (TdP) based on varying levels of documentation include the beta-agonists. Beta-agonists may cause cardiovascular effects, particularly when used in high doses and/or when associated with hypokalemia.
Acebutolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Acetaminophen; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
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: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists. (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.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Aspirin, ASA; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Atenolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Atenolol; Chlorthalidone: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
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.
Beta-adrenergic blockers: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Betaxolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Bisoprolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Brimonidine; Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Budesonide; Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects. (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
Bumetanide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Caffeine; Sodium Benzoate: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Carteolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Carvedilol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Chlordiazepoxide; Clidinium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Cisapride: (Contraindicated) QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for TdP, use of other drugs that might increase the QT interval is contraindicated with cisapride. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses and/or when associated with hypokalemia.
Cocaine: (Moderate) Additive effects and increased toxicity might be observed when using cocaine with beta-agonists, which are sympathomimetic agents. The combined use of these agents may have the potential for additive adrenergic stimulation and side effects, such as nervousness, insomnia, palpitations, or adverse cardiovascular 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.
Dorzolamide; Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Ergotamine; Caffeine: (Moderate) Caffeine may enhance the cardiac inotropic effects of beta-agonists.
Esmolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Ethacrynic Acid: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Flavoxate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Formoterol: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
Formoterol; Mometasone: (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
Furosemide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
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. (Major) Formoterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist for any reason, as overdose may result. Coadministration can result in overdosage. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with inhaled short-acting beta-2 agonists (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking formoterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if formoterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual. Use formoterol and drugs known to prolong the QTc interval together with extreme caution; this combination may increase the risk of cardiovascular effects and ventricular arrhythmias; this includes combination with other beta-agonists.
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: (Major) Indacaterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist, such as olodaterol, for any reason, as overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with an inhaled short-acting beta-2 agonist (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking indacaterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if indacaterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual.
Indacaterol; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects. (Major) Indacaterol should not be used in conjunction with other medications containing a long-acting beta-2 agonist, such as olodaterol, for any reason, as overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Acute symptoms should be treated with an inhaled short-acting beta-2 agonist (SABA) such as albuterol. SABAs should not be used on a regular basis (e.g., 4 times a day) while taking indacaterol. Increasing SABA use is a sign of deteriorating disease for which prompt medical attention is required. Prompt re-evaluation of the patient and their COPD treatment regimen should occur if indacaterol no longer controls symptoms of bronchoconstriction, the patient's SABA rescue becomes less effective, or the patient requires more SABA rescue doses than usual.
Isocarboxazid: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
Ketoconazole: (Moderate) Monitor for an increase in olodaterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase olodaterol exposure. No dose adjustment of olodaterol is necessary. In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol inhalation maximum plasma concentrations and AUC was observed. No dose adjustment is necessary. Olodaterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
Labetalol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Levobunolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Levoketoconazole: (Moderate) Monitor for an increase in olodaterol-related adverse effects, including increased heart rate and QT prolongation, if coadministered with ketoconazole. Coadministration may increase olodaterol exposure. No dose adjustment of olodaterol is necessary. In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol inhalation maximum plasma concentrations and AUC was observed. No dose adjustment is necessary. Olodaterol, as with other long-acting beta-agonists, should be administered with extreme caution to patients being treated with drugs known to prolong the QTc interval like ketoconazole because the effect of adrenergic agonists on the cardiovascular system may be potentiated.
Levothyroxine: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Linezolid: (Moderate) Linezolid may enhance the hypertensive effect of beta-agonists. Closely monitor for increased blood pressure during coadministration. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Therefore, linezolid has the potential for interaction with adrenergic agents, such as the beta-agonists.
Liothyronine: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Loop diuretics: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Lopinavir; Ritonavir: (Moderate) Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir.
Methacholine: (Major) Discontinue use of olodaterol 48 hours before a methacholine challenge test. Beta-agonists inhibit the airway response to 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.
Metoprolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Monoamine oxidase inhibitors: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
Nadolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Nebivolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Nebivolol; Valsartan: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Neostigmine; Glycopyrrolate: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Nirmatrelvir; Ritonavir: (Moderate) Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir.
Oxybutynin: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Phenelzine: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Pindolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Procarbazine: (Major) Procarbazine has MAOI activity and the cardiovascular effects of beta-2 agonists may be potentiated by concomitant use of MAOIs. Although no data are available, procarbazine may interact similarly. Close observation for such effects is prudent, particularly if beta-agonists are administered within two weeks of stopping the MAOI.
Propantheline: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Propranolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Racepinephrine: (Major) Racepinephrine is a sympathomimetic drug with agonist actions at both the alpha and beta receptors. Patients using prescription beta-agonists for the treatment of asthma should generally avoid the concurrent use of racepinephrine inhalation since additive cardiovascular and nervous system adverse effects are possible, some which may be undesirable.
Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetic agents was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and respiratory adrenergic agents (e.g., the beta-agonists). Although sympathomimetic agents are contraindicated for use with traditional non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. However, the cardiovascular effects of beta-2 agonists may be potentiated by concomitant use of MAOIs. At least one case of hypertension occurred in a patient with previous episodes of high blood pressure who was receiving albuterol and selegiline, a selective MAOI related to rasagiline, concurrently. Close observation for such effects is prudent, particularly if beta-2 agonists are administered during or within 2 weeks of use of an MAOI.
Ribociclib: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as olodaterol as compared to short-acting beta-agonists.
Ribociclib; Letrozole: (Moderate) Due to a possible risk for QT prolongation, ribociclib and long-acting beta-agonists should be used together cautiously. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval like ribociclib. This risk may be more clinically significant with long-acting beta-agonists such as olodaterol as compared to short-acting beta-agonists.
Ritonavir: (Moderate) Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir.
Scopolamine: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Theophylline, Aminophylline: (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, ((e.g., theophylline and aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated. (Moderate) Beta-agonists are commonly used in conjunction with aminophylline or theophylline therapy. Concomitant use can cause additive CNS stimulation; some patients may experience tremor or nervousness with combined use. More serious effects are rare, but may result in additive cardiovascular effects such as increased blood pressure and heart rate. Methylxanthine derivatives, (e.g., theophylline, aminophylline) may rarely aggravate the hypokalemic effect seen with beta-agonists. Consider checking potassium levels if clinically indicated.
Thiazide diuretics: (Minor) Hypokalemia associated with thiazide diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, use caution when coadministering beta-agonists with thiazide diuretics and monitor serum potassium as clinically indicated.
Thyroid hormones: (Moderate) Monitor blood pressure and heart rate during concomitant beta-agonist and thyroid hormone use. Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Timolol: (Moderate) Beta-blockers will block the pulmonary effects of inhaled beta-agonists, and in some cases may exacerbate bronchospasm in patients with reactive airways. Beta-agonists can sometimes increase heart rate or have other cardiovascular effects, particularly when used in high doses or if hypokalemia is present. Use of a beta-1-selective (cardioselective) beta blocker is recommended whenever possible when this combination of drugs must be used together. Monitor the patient's lung and cardiovascular status closely. Beta-agonists and beta-blockers are pharmacologic opposites and will counteract each other to some extent when given concomitantly, especially when non-cardioselective beta blockers are used.
Torsemide: (Moderate) Use beta-agonists and loop diuretics with caution due to risk for ECG changes and/or hypokalemia. The ECG changes and/or hypokalemia that may result from administration of loop diuretics can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Tranylcypromine: (Moderate) Use beta-agonists with caution in patients receiving concomitant monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with MAOIs because the action of beta-agonists on the cardiovascular system may be potentiated.
Trihexyphenidyl: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.

STIOLTO RESPIMAT/Tiotropium, Olodaterol Respiratory (Inhalation) Spray Met: 1actuation, 2.5-2.5mcg

5 mcg/day of tiotropium and 5 mcg/day of olodaterol via oral inhalation (i.e., 2 inhalations/day of Stiolto Respimat 2.5/2.5).

5 mcg/day of tiotropium and 5 mcg/day of olodaterol via oral inhalation (i.e., 2 inhalations/day of Stiolto Respimat 2.5/2.5).

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Not indicated.

Not indicated.

Tiotropium is a respiratory antimuscarinic or long-acting antimuscarinic antagonist (LAMA), which is often referred to as an anticholinergic; olodaterol is a long-acting, selective beta-2 agonist (LABA).
Tiotropium: 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 in COPD. 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—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.
Olodaterol: Olodaterol is a long-acting beta-2 adrenergic agonist (LABA). Beta-2 receptors are present in large numbers in the lungs and are located on bronchiolar smooth muscle. Stimulation of beta-2 receptors in the lung causes relaxation of bronchial smooth muscle, which produces bronchodilation and a resultant increase in bronchial airflow. These effects are believed to be mediated, in part, by increased activity of adenyl cyclase, an intracellular enzyme responsible for the formation of cyclic-3',5'-adenosine monophosphate (cAMP).

Tiotropium; olodaterol is administered by oral inhalation. The pharmacokinetic parameters for the combination product tiotropium; olodaterol (Stiolto Respimat) were similar to those observed when each active substance was administered separately.
Tiotropium: A pharmacokinetic study in patients with COPD evaluating once-daily tiotropium delivered from the inhalation spray (5 mcg dose) and as inhalation powder (18 mcg dose) resulted in a similar systemic exposure between the two products. 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. Metabolic transformation is not known. The mean plasma terminal elimination half-life is 5 to 6 days. In a pharmacokinetic study, 74% of intravenously administered tiotropium was excreted in urine as unchanged drug. Increases in FEV1 have been shown to be dose-related. Trough FEV1 and FVC have been shown to average greater than 12% over baseline one week after tiotropium administration.
Olodaterol: Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. Of the six metabolites identified, only the unconjugated demethylation product binds to beta-2 receptor. This metabolite, however, is undetectable in plasma after chronic inhalation of the recommended therapeutic dose. Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following IV administration and inhalation in contrast is 22 hours and 45 hours, respectively, indicating that the latter is determined by absorption rather than by elimination processes. The effective half-life is 7.5 hours. Following IV administration of [14C]-labeled olodaterol, 38% of the radioactive dose was recovered in the urine and 53% was recovered in feces. The amount of unchanged olodaterol recovered in the urine after IV administration was 19%. Following oral administration, only 9% of olodaterol and/or its metabolites was recovered in urine, while the major portion was recovered in feces (84%). More than 90% of the dose was excreted within 6 and 5 days following IV and oral administration, respectively. Following inhalation, excretion of unchanged olodaterol in urine within the dosing interval in healthy volunteers at steady state accounted for 5% to 7% of the dose.
 
Tiotropium -- 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 (only 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.
 
Olodaterol -- Affected Cytochrome P450 (CYP 450) enzymes and drug transporters: CYP2C9, CYP2C8, CYP3A4, UGT2B7, UGT1A1, UGT1A7, and UGT1A9
Olodaterol is substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation. CYP450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase (UGT) isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides. However, olodaterol has not been shown to induce or inhibit any CYP450 enzymes or drug transporters.

Tiotropium: Following 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—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 levels are not used to monitor clinical response. Peak concentrations are achieved in 5 minutes, and trough levels in < 60 minutes. With dosing compliance of the inhalation formulation, steady-state is achieved within the first week of therapy.
Olodaterol: Olodaterol reaches maximum plasma concentrations generally within 10 to 20 minutes following drug inhalation. In healthy volunteers, the absolute bioavailability of olodaterol following inhalation was estimated to be approximately 30%, whereas the absolute bioavailability was below 1% when given as an oral solution. Thus, the systemic availability of olodaterol after inhalation is mainly determined by lung absorption, while any swallowed portion of the dose only negligibly contributes to systemic exposure.

Use caution when administering tiotropium; olodaterol to women who are breast-feeding. It is unknown whether tiotropium or olodaterol is excreted in breast milk; however, other beta-agonists have been detected in human breast milk. However, because of low systemic tiotropium concentrations in the mother after inhalation and poor absorption from the gastrointestinal tract (i.e. 2% to 3%), it is unlikely that clinically significant exposure to tiotropium will occur in a breast-feeding infant. Olodaterol and/or its metabolites are excreted into the milk of lactating rats and excretion of olodaterol and/or its metabolites into human milk is probable. 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.