tiotropium/olodaterol inhaled (Rx)

• abiraterone abiraterone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias
• acebutolol acebutolol, olodaterol inhaled. Either decreases effects of the other by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Beta-blockers and olodaterol may interfere with the effect of each other when administered concurrently. Beta-blockers may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
• albuterol albuterol and olodaterol inhaled both increase sympathetic (adrenergic) effects, including increased blood pressure and heart rate. Use Caution/Monitor. Caution with coadministration of adrenergic drugs by any route because of additive sympathetic effects

tiotropium decreases levels of aripiprazole by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of aripiprazole by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of benperidol by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of chlorpromazine by pharmacodynamic antagonism. Use Caution/Monitor.

chlorpromazine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

clozapine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor.

tiotropium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of droperidol by pharmacodynamic antagonism. Use Caution/Monitor.

fluphenazine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of fluphenazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of haloperidol by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of haloperidol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of iloperidone by pharmacodynamic antagonism. Use Caution/Monitor.

iloperidone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

tiotropium decreases levels of loxapine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of olanzapine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of paliperidone by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

paliperidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

perphenazine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

tiotropium decreases levels of perphenazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of pimozide by pharmacodynamic antagonism. Use Caution/Monitor.

pimozide increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of prochlorperazine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of promethazine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of quetiapine by pharmacodynamic antagonism. Use Caution/Monitor.

quetiapine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

risperidone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

risperidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of thioridazine by pharmacodynamic antagonism. Use Caution/Monitor.

thioridazine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

tiotropium decreases levels of thiothixene by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of thiothixene by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of trifluoperazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

trifluoperazine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of ziprasidone by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

ziprasidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

Minor (3)

• dimenhydrinate dimenhydrinate increases toxicity of tiotropium by pharmacodynamic synergism. Minor/Significance Unknown. Additive anticholinergic effects.
• donepezil donepezil decreases effects of tiotropium by pharmacodynamic antagonism. Minor/Significance Unknown.
• galantamine galantamine decreases effects of tiotropium by pharmacodynamic antagonism. Minor/Significance Unknown.

• abiraterone Monitor Closely (1) abiraterone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias
• acebutolol Monitor Closely (1) acebutolol, olodaterol inhaled. Either decreases effects of the other by Mechanism: pharmacodynamic antagonism. Use Caution/Monitor. Beta-blockers and olodaterol may interfere with the effect of each other when administered concurrently. Beta-blockers may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g. as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
• albuterol Monitor Closely (2) albuterol and olodaterol inhaled both increase QTc interval. Use Caution/Monitor.

tiotropium decreases levels of aripiprazole by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of aripiprazole by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of benperidol by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of chlorpromazine by pharmacodynamic antagonism. Use Caution/Monitor.

chlorpromazine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

clozapine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor.

tiotropium decreases levels of clozapine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of droperidol by pharmacodynamic antagonism. Use Caution/Monitor.

droperidol increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

fluphenazine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of fluphenazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of haloperidol by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of haloperidol by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of iloperidone by pharmacodynamic antagonism. Use Caution/Monitor.

iloperidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of loxapine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of olanzapine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of paliperidone by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

paliperidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

perphenazine and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

tiotropium decreases levels of perphenazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of pimozide by pharmacodynamic antagonism. Use Caution/Monitor.

pimozide increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of prochlorperazine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of promethazine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of quetiapine by pharmacodynamic antagonism. Use Caution/Monitor.

quetiapine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

risperidone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

risperidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

tiotropium decreases levels of thioridazine by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of thioridazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of thiothixene by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

tiotropium decreases levels of thiothixene by pharmacodynamic antagonism. Use Caution/Monitor.

tiotropium decreases levels of trifluoperazine by inhibition of GI absorption. Applies only to oral form of both agents. Use Caution/Monitor.

trifluoperazine increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

ziprasidone and olodaterol inhaled both increase QTc interval. Use Caution/Monitor. Drugs that prolong the QTc interval and may potentiate the effects of beta2 agonists on the cardiovascular system; increased risk of ventricular arrhythmias

ziprasidone increases effects of tiotropium by pharmacodynamic synergism. Use Caution/Monitor. Additive anticholinergic effects, possible hypoglycemia.

Adverse Effects

Incidence similar to individual components

>10%

1-10%

≤3%

• Dehydration
• Dizziness, insomnia
• Glaucoma, intraocular pressure increased, vision blurred
• Atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension
• Epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis
• Dry mouth, constipation, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, intestinal obstruction including paralytic ileus
• Rash, pruritus, angioneurotic edema, urticaria, skin infection, and skin ulcer, dry skin, hypersensitivity (including immediate reactions)
• Arthralgia, joint swelling
• Urinary retention, dysuria, and urinary tract infection

Warnings

Black Box Warnings

Asthma-related death

• Long-acting beta2-adrenergic agonists (LABAs), such as olodaterol, increase the risk for asthma-related death
• A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths; this finding is considered a class effect of all LABAs, including olodaterol
• Not to be used as a rescue therapy to treat acute bronchospasm; indicated for COPD maintenance therapy
• Safety and efficacy not established in patients with asthma; NOT approved for treatment of asthma

Contraindications

Use of a LABA without an inhaled corticosteroid; tiotropium/olodaterol inhaled is not indicated for asthma

Hypersensitivity to tiotropium ipratropium, olodaterol, or other ingredients

Postmarketing experience with tiotropium, immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash reported; hypersensitivity reactions were also reported in clinical trials with tiotropium/olodaterol inhaled

Cautions

Safety and efficacy in patients with asthma not established; not indicated for asthma; monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death (see Black Box Warnings)

Available data do not suggest an increased risk of death with use of LABA in patients with COPD

Do not initiate in acutely deteriorating COPD

Do not use 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 & Lactation

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 condition

Pregnancy 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.