for relief of acute symptoms; concomitant short-acting beta2­ agonists can be used as needed for acute relief Do not exceed the recommended dose; excessive use, or use in conjunction with other medications containing LABA, can result in clinically significant cardiovascular effects and may be fatal Immediate hypersensitivity reactions reported; discontinue immediately and consider alternatives if immediate hypersensitivity reactions, including angioedema, bronchospasm, or anaphylaxis, occur (see Contraindications) Life-threatening paradoxical bronchospasm can occur; discontinue immediately Caution with cardiovascular or convulsive disorders, hyperthyroidism, or diabetes mellitus, and in patients who are unusually responsive to sympathomimetic amines Drug is an anticholinergic and may increase intraocular pressure; this may result in precipitation or worsening of narrow-angle glaucoma; therefore, drug should be used with caution in patients with narrow-angle glaucoma; avoid spraying into eyes; if a patient sprays drug into their eyes they may cause acute eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos, or colored images in association with red eyes from conjunctival or corneal congestion; advise patients to consult their physician immediately if symptoms develop while using drug Worsening of urinary retention may occur; caution with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs May cause hyperglycemia Beta2-adrenergic agonists may produce significant hypokalemia in some patients (possibly through intracellular shunting) which has potential to produce adverse cardiovascular effects; decrease in serum potassium is usually transient, not requiring supplementation Monitor patients with moderate-to-severe renal impairment (≤60 mL/min) for anticholinergic adverse effects; tiotropium is predominantly excreted renally Cardiovascular effects Can produce a clinically significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, and/or symptoms If symptoms occur, may need to discontinue therapy; there is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischemia associated with albuterol In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression Therapy should be used with caution in patients with cardiovascular disorders; especially coronary insufficiency, cardiac arrhythmias, and hypertension Drug interactions overview Additional adrenergic drugs by any route may potentiate sympathetic effects of olodaterol Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of olodaterol ECG changes and/or hypokalemia may result from non-potassium sparing diuretics administration (loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the beta-agonist dose exceeds the recommended dose Exercise extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants or other drugs cause QT prolongation; drugs known to prolong the QTc interval may increase the risk of ventricular arrhythmias Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients; use with caution May interact additively with concomitantly used anticholinergics; avoid use with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects Pregnancy There are no adequate and well-controlled clinical studies with or its individual components, tiotropium bromide and olodaterol, in pregnant women to inform of drug-associated risk of adverse pregnancy-related outcomes Use during pregnancy only if the potential benefit justifies the potential risk to the fetus Labor and delivery There are no adequate and well-controlled human studies that have investigated effects on preterm labor or labor at term; because of potential for beta-agonist interference with uterine contractility, use during labor should be restricted to those patients in whom benefits clearly outweigh risks Animal data Based on animal reproduction studies, no structural abnormalities observed when tiotropium was administered by inhalation to pregnant rats and rabbits during the period of organogenesis at doses 790 and 8 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) Increased postimplantation loss observed in rats and rabbits administered tiotropium at maternally toxic doses 430 times and 40 times the MRHDID, respectively Based on animal studies, olodaterol was not teratogenic when administered to pregnant rats or rabbits during organogenesis at inhalation doses of approximately 2731 or 1353 times the MRHDID (on an AUC basis), in rats or rabbits, respectively Lactation There are no data on presence of tiotropium or olodaterol in human milk, effects on breastfed infant, or on milk production Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal conditionPregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Tiotropium: Long-acting antimuscarinic agent, often referred to as anticholinergic; inhibits M3-receptors at smooth muscle, leading to bronchodilation Olodaterol: Long-acting beta2-adrenergic agonist (LABA); activates specific beta2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cAMP and smooth muscle relaxation Absorption Tiotropium ~33% of the inhaled dose reaches the systemic circulation Absolute bioavailability (oral solution): 2-3% Peak plasma time: 5-7 minutes after inhalation Olodaterol ~30% of the inhaled dose reaches the systemic circulation Absolute bioavailability (oral solution): <1% Peak plasma time: 10-20 minutes after inhalation Distribution Tiotropium Protein bound: 72% Vd: 32 L/kg Olodaterol Protein bound: 60% Vd: 1110 L Metabolism Tiotropium: 25% metabolized by CYP2D6 and 3A4, then subsequent glutathione conjugation Olodaterol Substantially metabolized by direct glucuronidation and by O-demethylation at the methoxy moiety followed by conjugation Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol Uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides Elimination Tiotropium Half-life (inhaled): 25 hr (terminal) Total clearance: 880 mL/min (IV administration) Excretion: 18.6% urine; remainder being mainly nonabsorbed drug in the gut that is eliminated via the feces Olodaterol Half-life (inhaled): 45 hr (terminal); 7.5 hr (effective) Total clearance: 872 mL/min Renal clearance: 173 mL/min Excretion: 9% urine; remainder being mainly nonabsorbed drug in the gut that is eliminated via the feces Oral Inhalation Administration Oral inhalation only See prescribing information for full instructions Priming inhaler When using the unit for the first time, insert the cartridge into inhaler and prime the unit by actuating the inhaler toward the ground until an aerosol cloud is visible and then repeat the process 3 more times If not used for >3 days, patients are to actuate the inhaler once to prepare the inhaler for use If not used for >21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process 3 more times to prepare the inhaler for use Missed dose: Take it as soon as possible; do not take more than 1 dose (2 puffs) in 24 hours Storage Store at controlled room temperature at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) Avoid freezing No images available for this drug. 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