Tiotropium bromide and olodaterol

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Tiotropium bromide and olodaterol
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vishal Devarkonda, M.B.B.S[2]

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Black Box Warning

WARNING: ASTHMA-RELATED DEATH
See full prescribing information for complete Boxed Warning.
  • Long-acting beta2-adrenergic agonists (LABA) such as olodaterol increase the risk of asthma-related death.
  • Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol.
  • This finding with salmeterol is considered a class effect of all LABAs, including olodaterol.
  • The safety and efficacy of tiotropium bromide and olodaterol in patients with asthma have not been established. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.

Overview

Tiotropium bromide and olodaterol is a combination of an anticholinergic and a long-acting beta2-adrenergic agonist that is FDA approved for the treatment of of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nasopharyngitis, cough, and back pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Tiotropium bromide and olodaterol is indicated for long-term, once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations of Use:

Dosing Information

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of tiotropium bromide and olodaterol in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of tiotropium bromide and olodaterol in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Tiotropium bromide and olodaterol FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of tiotropium bromide and olodaterol in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of tiotropium bromide and olodaterol in pediatric patients.

Contraindications

Warnings

WARNING: ASTHMA-RELATED DEATH
See full prescribing information for complete Boxed Warning.
  • Long-acting beta2-adrenergic agonists (LABA) such as olodaterol increase the risk of asthma-related death.
  • Data from a large, placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol.
  • This finding with salmeterol is considered a class effect of all LABAs, including olodaterol.
  • The safety and efficacy of tiotropium bromide and olodaterol in patients with asthma have not been established. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.

Adverse Reactions

Clinical Trials Experience

LABA, such as olodaterol, one of the active components in tiotropium bromide and olodaterol, increase the risk of asthma-related death. Tiotropium bromide and olodaterol is not indicated for the treatment of asthma.

Because clinical trials are conducted under widely varying conditions, the incidence of adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidences in the clinical trials of another drug and may not reflect the incidences observed in practice.

The clinical program for tiotropium bromide and olodaterol included 7151 subjects with COPD in two 52-week active-controlled trials, one 12-week placebo-controlled trial, three 6-week placebo-controlled cross-over trials, and four additional trials of shorter duration. A total of 1988 subjects received at least 1 dose of tiotropium bromide and olodaterol. Adverse reactions observed in the ≤12-week trials were consistent with those observed in the 52-week trials, which formed the primary safety database.

The primary safety database consisted of pooled data from the two 52-week double-blind, active-controlled, parallel group confirmatory clinical trials. These trials included 5162 adult COPD patients (72.9% males and 27.1% females) 40 years of age and older. Of these patients, 1029 were treated with tiotropium bromide and olodaterol once daily. The tiotropium bromide and olodaterol group was composed of mostly Caucasians (71.1%) with a mean age of 63.8 years and a mean percent predicted FEV1 at baseline of 43.2%. In these two trials, tiotropium 5 mcg and olodaterol 5 mcg were included as active control arms and no placebo was used.

In these two clinical trials, 74% of patients exposed to tiotropium bromide and olodaterol reported an adverse reaction compared to 76.6% and 73.3% in the olodaterol 5 mcg and tiotropium 5 mcg groups, respectively. The proportion of patients who discontinued due to an adverse reaction was 7.4% for tiotropium bromide and olodaterol treated patients compared to 9.9% and 9.0% for olodaterol 5 mcg and tiotropium 5 mcg treated patients. The adverse reaction most commonly leading to discontinuation was worsening COPD. The most common serious adverse reactions were COPD exacerbation and pneumonia.

Table 1 shows all adverse drug reactions that occurred with an incidence of >3% in the tiotropium bromide and olodaterol treatment group and a higher incidence rate than the active comparator groups listed.

This image is provided by the National Library of Medicine

Other adverse drug reactions in patients receiving tiotropium bromide and olodaterol that occurred in ≤3% of patients in clinical studies are listed below:

Respiratory, thoracic, and mediastinal disorders: epistaxis, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis

Postmarketing Experience

There is limited information regarding Tiotropium bromide and olodaterol Postmarketing Experience in the drug label.

Drug Interactions

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies with tiotropium bromide and olodaterol or its individual components, tiotropium bromide and olodaterol, in pregnant women. Animal reproduction studies were conducted with the individual components of tiotropium bromide and olodaterol, tiotropium bromide and olodaterol. Tiotropium bromide and olodaterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Tiotropium

No evidence of structural alterations was observed in rats and rabbits at approximately 790 and 8 times the recommended human daily inhalation dose (RHDID; on a mcg/m2 basis at maternal inhalation doses of 1471 and 7 mcg/kg/day in rats and rabbits, respectively). However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at approximately 40 times the RHDID (on a mcg/m2 basis at a maternal inhalation dose of 78 mcg/kg/day). In rabbits, tiotropium caused an increase in post-implantation loss at approximately 430 times the RHDID (on a mcg/m2 basis at a maternal inhalation dose of 400 mcg/kg/day). Such effects were not observed at approximately 5 and 95 times the RHDID (on a mcg/m2 basis at maternal inhalation doses of 9 and 88 mcg/kg/day in rats and rabbits, respectively).

Olodaterol

Olodaterol was not teratogenic in rats at approximately 2731 times the RHDID (on an AUC basis at a maternal inhalation dose of 1054 mcg/kg/day). Placental transfer of olodaterol was observed in pregnant rats.

Olodaterol has been shown to be teratogenic in New Zealand rabbits at approximately 7130 times the RHDID in adults (on an AUC basis at a maternal inhalation dose of 2489 mcg/kg/day). Olodaterol exhibited the following fetal toxicities: enlarged or small heart atria or ventricles, eye abnormalities, and split or distorted sternum. No significant effects occurred at approximately 1353 times the RHDID in adults (on an AUC basis at a maternal inhalation dose of 974 mcg/kg/day).
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tiotropium bromide and olodaterol in women who are pregnant.

Labor and Delivery

There are no adequate and well-controlled human studies that have investigated the effects of tiotropium bromide and olodaterol on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of tiotropium bromide and olodaterol during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

Clinical data from nursing women or infants exposed to tiotropium bromide and olodaterol or its individual active components are not available. Tiotropium, olodaterol, and metabolites of olodaterol are excreted into the milk of lactating rats. It is not known whether these compounds are excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if tiotropium bromide and olodaterol is administered to a nursing woman.

Pediatric Use

COPD does not normally occur in children. The safety and effectiveness of tiotropium bromide and olodaterol in the pediatric population has not been established.

Geriatic Use

Based on available data, no adjustment of tiotropium bromide and olodaterol dosage in geriatric patients is warranted.

Of the 1029 patients who received tiotropium bromide and olodaterol at the recommended dose once daily in the clinical studies from the pooled 1-year database, 525 (51.0%) were <65 years of age, 407 (39.6%) were 65 to <75, 96 (9.3%) were 75 to <85, and 1 (0.1%) was ≥85.

No overall differences in effectiveness were observed, and in the 1-year pooled data, the adverse drug reaction profiles were similar in the older population compared to the patient population overall.

Gender

There is no FDA guidance on the use of Tiotropium bromide and olodaterol with respect to specific gender populations.

Race

There is no FDA guidance on the use of Tiotropium bromide and olodaterol with respect to specific racial populations.

Renal Impairment

No dose adjustment is required for patients with renal impairment. However, patients with moderate to severe renal impairment (creatinine clearance of <60 mL/min) treated with tiotropium bromide and olodaterol should be monitored closely for anticholinergic side effects.

Hepatic Impairment

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

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tiotropium bromide and olodaterol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tiotropium bromide and olodaterol in patients who are immunocompromised.

Administration and Monitoring

Administration

  • For oral inhalation only.
  • Prior to first use, the tiotropium bromide and olodaterol cartridge is inserted into the tiotropium bromide and olodaterol inhaler and the unit is primed.
  • When using the unit for the first time, patients are to actuate the inhaler toward the ground until an aerosol cloud is visible and then repeat the process three more times. The unit is then considered primed and ready for use.
  • If not used for more than 3 days, patients are to actuate the inhaler once to prepare the inhaler for use.
  • If not used for more than 21 days, patients are to actuate the inhaler until an aerosol cloud is visible and then repeat the process three more times to prepare the inhaler for use.
  • No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given tiotropium bromide and olodaterol should be monitored closely for anticholinergic effects.

Monitoring

There is limited information regarding Tiotropium bromide and olodaterol Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Tiotropium bromide and olodaterol and IV administrations.

Overdosage

The risks associated with overdosage for the individual components described below apply to the combination drug of tiotropium bromide and olodaterol.

Tiotropium

High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Dry mouth/throat and dry nasal mucosa occurred in a dose-dependent [10-40 mcg daily] manner, were observed following 14-day dosing of up to 40 mcg tiotropium bromide inhalation solution in healthy subjects.

Olodaterol

The expected signs and symptoms with overdosage of olodaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., myocardial ischemia, angina pectoris, hypertension or hypotension, tachycardia, arrhythmias, palpitations, dizziness, nervousness, insomnia, anxiety, headache, tremor, dry mouth, muscle spasms, nausea, fatigue, malaise, hypokalemia, hyperglycemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of olodaterol.

Treatment of overdosage consists of discontinuation of tiotropium bromide and olodaterol together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of tiotropium bromide and olodaterol. Cardiac monitoring is recommended in cases of overdosage.

Pharmacology

Mechanism of Action

The properties described below for the individual components apply to the combination of tiotropium bromide and olodaterol. These drugs represent 2 different classes of medication (an anticholinergic and a beta-agonist) that have different effects on clinical and physiological indices.

Tiotropium

Tiotropium is a long-acting, muscarinic antagonist which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

Olodaterol

Olodaterol is a long-acting beta2-adrenergic agonist (LABA). The compound exerts its pharmacological effects by binding and activation of beta2-adrenoceptors after topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3’, 5’ adenosine monophosphate (cAMP). Elevated levels of cAMP induce bronchodilation by relaxation of airway smooth muscle cells. In vitro studies have shown that olodaterol has 241-fold greater agonist activity at beta2-adrenoceptors compared to beta1-adrenoceptors and 2299-fold greater agonist activity compared to beta3-adrenoceptors. The clinical significance of these findings is unknown.

Beta-adrenoceptors are divided into three subtypes: beta1-adrenoceptors predominantly expressed on cardiac muscle, beta2-adrenoceptors predominantly expressed on airway smooth muscle, and beta3-adrenoceptors predominantly expressed on adipose tissue. Beta2-agonists cause bronchodilation. Although the beta2-adrenoceptor is the predominant adrenergic receptor in the airway smooth muscle, it is also present on the surface of a variety of other cells, including lung epithelial and endothelial cells and in the heart. The precise function of beta2-receptors in the heart is not known, but their presence raises the possibility that even highly selective beta2-agonists may have cardiac effects.

Structure

The drug substance tiotropium bromide monohydrate is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is:

This image is provided by the National Library of Medicine

Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O.

The drug substance olodaterol hydrochloride is chemically described as 2H-1,4-Benzoxazin-3H(4H)-one, 6-hydroxy-8-[(1R)-1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethyl]-amino]ethyl]-, monohydrochloride. Olodaterol hydrochloride is a white to off-white powder that is sparingly-slightly soluble in water and slightly soluble in ethanol. The molecular weight is 422.9 g/mole (salt): 386.5 g/mole (base), and the molecular formula is C21H26N2O5 x HCl as a hydrochloride. The conversion factor from salt to free base is 1.094. The structural formula is:

This image is provided by the National Library of Medicine

Pharmacodynamics

Cardiac Electrophysiology

Tiotropium Bromide and Olodaterol

In two 52-week randomized, double-blind trials using tiotropium bromide and olodaterol that enrolled 5162 patients with COPD, ECG assessments were performed post-dose on days 1, 85, 169, and 365. In a pooled analysis the number of subjects with changes from baseline-corrected QT interval of >30 msec using both the Bazett (QTcB) and Fredericia (QTcF), corrections of QT for heart rate were not different for the tiotropium bromide and olodaterol group compared to olodaterol 5 mcg and tiotropium 5 mcg across the assessments conducted.

Tiotropium

The effect of tiotropium dry powder for inhalation on QT interval was also evaluated in a randomized, placebo- and positive-controlled crossover study in 53 healthy volunteers. Subjects received tiotropium inhalation powder 18 mcg, 54 mcg (3 times the recommended dose), or placebo for 12 days. ECG assessments were performed at baseline and throughout the dosing interval following the first and last dose of study medication. Relative to placebo, the maximum mean change from baseline in study-specific QTc interval was 3.2 msec and 0.8 msec for tiotropium inhalation powder 18 mcg and 54 mcg, respectively. No subject showed a new onset of QTc >500 msec or QTc changes from baseline of ≥60 msec.

In a multicenter, randomized, double-blind trial using tiotropium dry powder for inhalation that enrolled 198 patients with COPD, the number of subjects with changes from baseline-corrected QT interval of 30–60 msec was higher in the tiotropium group as compared with placebo. This difference was apparent using both the Bazett (QTcB) [20 (20%) patients vs. 12 (12%) patients] and Fredericia (QTcF) [16 (16%) patients vs. 1 (1%) patient] corrections of QT for heart rate. No patients in either group had either QTcB or QTcF of >500 msec. Other clinical trials with tiotropium did not detect an effect of the drug on QTc intervals.

Olodaterol

The effect of olodaterol on the QT/QTc interval of the ECG was investigated in 24 healthy male and female volunteers in a double-blind, randomized, placebo- and active (moxifloxacin)- controlled study at single doses of 10, 20, 30, and 50 mcg. Dose-dependent QtcI (individual subject corrected QT interval) prolongation was observed. The maximum mean (one-sided 95% upper confidence bound) difference in QTcI from placebo after baseline correction was 2.5 (5.6) ms, 6.1 (9.2) ms, 7.5 (10.7) ms, and 8.5 (11.6) ms following doses of 10, 20, 30, and 50 mcg, respectively.

The effect of 5 mcg and 10 mcg olodaterol on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 772 patients in the 48-week, placebo-controlled phase 3 trials. There were no dose- or time-related trends or patterns observed for the magnitudes of mean changes in heart rate or premature beats. Shifts from baseline to the end of treatment in premature beats did not indicate meaningful differences between olodaterol 5 mcg, 10 mcg, and placebo.

Pharmacokinetics

When tiotropium bromide and olodaterol was administered by the inhalation route, the pharmacokinetic parameters for tiotropium and for olodaterol were similar to those observed when each active substance was administered separately.

Tiotropium:

Tiotropium is administered as an inhalation spray. Some of the pharmacokinetic data described below were obtained with higher doses than recommended for therapy.

Olodaterol

Olodaterol showed linear pharmacokinetics. On repeated once-daily inhalation, steady-state of olodaterol plasma concentrations was achieved after 8 days, and the extent of exposure was increased up to 1.8-fold as compared to a single dose.

Absorption

Tiotropium

Following inhalation of the solution by young healthy volunteers, urinary excretion data suggests that approximately 33% of the inhaled dose reaches the systemic circulation. Oral solutions of tiotropium have an absolute bioavailability of 2% to 3%. Food is not expected to influence the absorption of tiotropium for the same reason. Maximum tiotropium plasma concentrations were observed 5 to 7 minutes after inhalation.

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.

Distribution

Tiotropium

The drug has a plasma protein binding of 72% and shows a volume of distribution of 32 L/kg. Local concentrations in the lung are not known, but the mode of administration suggests substantially higher concentrations in the lung. Studies in rats have shown that tiotropium does not penetrate the blood-brain barrier.

Olodaterol

Olodaterol exhibits multi-compartmental disposition kinetics after inhalation as well as after intravenous administration. The volume of distribution is high (1110 L), suggesting extensive distribution into tissue. In vitro binding of [14C] olodaterol to human plasma proteins is independent of concentration and is approximately 60%.

Elimination

Metabolism

Tiotropium: The extent of metabolism is small. This is evident from a urinary excretion of 74% of unchanged substance after an intravenous dose to young healthy volunteers. Tiotropium, an ester, is nonenzymatically cleaved to the alcohol N-methylscopine and dithienylglycolic acid, both not binding to muscarinic receptors. In vitro experiments with human liver microsomes and human hepatocytes suggest that a fraction of the administered dose (74% of an intravenous dose is excreted unchanged in the urine, leaving 25% for metabolism) is metabolized by cytochrome P450-dependent oxidation and subsequent glutathione conjugation to a variety of Phase 2 metabolites. This enzymatic pathway can be inhibited by CYP2D6 and CYP3A4 inhibitors, such as quinidine, ketoconazole, and gestodene. 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 CYP1A1, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.

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 beta2-receptors. This metabolite, however, is not detectable in plasma after chronic inhalation of the recommended therapeutic dose. Cytochrome P450 isozymes CYP2C9 and CYP2C8, with negligible contribution of CYP3A4, are involved in the O-demethylation of olodaterol, while uridine diphosphate glycosyl transferase isoforms UGT2B7, UGT1A1, 1A7, and 1A9 were shown to be involved in the formation of olodaterol glucuronides.

Excretion

Tiotropium: The terminal half-life of tiotropium in COPD patients following once daily inhalation of 5 mcg tiotropium was approximately 25 hours. Total clearance was 880 mL/min after an intravenous dose in young healthy volunteers. Intravenously administered tiotropium bromide is mainly excreted unchanged in urine (74%). After inhalation of the solution by patients with COPD, urinary excretion is 18.6% (0.932 mcg) of the dose, the remainder being mainly non-absorbed drug in the gut that is eliminated via the feces. The renal clearance of tiotropium exceeds the creatinine clearance, indicating secretion into the urine. After chronic once-daily inhalation by COPD patients, pharmacokinetic steady state was reached by day 7 with no accumulation thereafter.

Olodaterol: Total clearance of olodaterol in healthy volunteers is 872 mL/min, and renal clearance is 173 mL/min. The terminal half-life following intravenous administration is 22 hours. The terminal half-life following inhalation in contrast is about 45 hours, indicating that the latter is determined by absorption rather than by elimination processes. However, the effective half-life at daily dose of 5 mcg calculated from Cmax from COPD patients is 7.5 hours. Following intravenous 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 intravenous 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 intravenous 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.

Drug Interactions

Tiotropium Bromide and Olodaterol:

Pharmacokinetic drug interaction studies with tiotropium bromide and olodaterol have not been performed; however, such studies have been conducted with individual components tiotropium and olodaterol.

When tiotropium and olodaterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately.

Tiotropium:

An interaction study with tiotropium (14.4 mcg intravenous infusion over 15 minutes) and cimetidine 400 mg three times daily or ranitidine 300 mg once-daily was conducted. Concomitant administration of cimetidine with tiotropium resulted in a 20% increase in the AUC0-4h, a 28% decrease in the renal clearance of tiotropium and no significant change in the Cmax and amount excreted in urine over 96 hours. Co-administration of tiotropium with ranitidine did not affect the pharmacokinetics of tiotropium.

Common concomitant medications (long-acting beta2-adrenergic agonists (LABA), inhaled corticosterioids (ICS)) used by patients with COPD were not found to alter the exposure to tiotropium.

Olodaterol:

Drug-drug interaction studies were carried out using fluconazole as a model inhibitor of CYP2C9 and ketoconazole as a potent P-gp (and CYP3A4, CYP2C8, CYP2C9) inhibitor.

Fluconazole:

Co-administration of 400 mg fluconazole once a day for 14 days had no relevant effect on systemic exposure to olodaterol.

Ketoconazole:

Co-administration of 400 mg ketoconazole once a day for 14 days increased olodaterol Cmax by 66% and AUC0-1 by 68%.

Tiotropium: Co-administration of tiotropium bromide, delivered as a fixed-dose combination with olodaterol, for 21 days had no relevant effect on systemic exposure to olodaterol, and vice versa.

Specific Populations

Olodaterol:

A pharmacokinetic meta-analysis showed that no dose adjustment is necessary based on the effect of age, gender, and weight on systemic exposure in COPD patients after inhalation of olodaterol.

Geriatric Patients

Tiotropium: As expected for all predominantly renally excreted drugs, advancing age was associated with a decrease of tiotropium renal clearance (347 mL/min in COPD patients <65 years to 275 mL/min in COPD patients ≥65 years). This did not result in a corresponding increase in AUC0-6,ss and Cmax,ss values.

Renal Impairment

Tiotropium: Following inhaled administration of therapeutic doses of tiotropium to steady-state to patients with COPD, mild renal impairment (creatinine clearance 60 - <90 mL/min) resulted in 23% higher AUC0-6,ss and 17% higher Cmax,ss values. Moderate renal impairment (creatinine clearance 30 - <60 mL/min) resulted in 57% higher AUC0-6,ss and 31% higher Cmax,ss values compared to COPD patients with normal renal function (creatinine clearance >90 mL/min). In COPD patients with severe renal impairment (CLCR <30 mL/min), a single intravenous administration of tiotropium bromide resulted in 94% higher AUC0-4 and 52% higher Cmax compared to COPD patients with normal renal function.

Olodaterol: Olodaterol levels were increased by approximately 40% in subjects with severe renal impairment. A study in subjects with mild and moderate renal impairment was not performed.

Hepatic Impairment

Tiotropium: The effects of hepatic impairment on the pharmacokinetics of tiotropium were not studied.

Olodaterol: Subjects with mild and moderate hepatic impairment showed no changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. A study in subjects with severe hepatic impairment was not performed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tiotropium Bromide and Olodaterol:

No studies of the carcinogenicity, in vitro mutagenicity, or impairment of fertility were conducted with tiotropium bromide and olodaterol, however, studies are available for the individual components, tiotropium and olodaterol.

Tiotropium:

No evidence of tumorigenicity was observed in a 104-week inhalation study in rats at tiotropium doses up to 59 mcg/kg/day, in an 83-week inhalation study in female mice at doses up to 145 mcg/kg/day, and in a 101-week inhalation study in male mice at doses up to 2 mcg/kg/day. These doses correspond to approximately 30, 40, and 0.5 times the recommended human daily inhalation dose (RHDID) on a mcg/m2 basis, respectively. Tiotropium bromide demonstrated no evidence of mutagenicity or clastogenicity in the following assays: the bacterial gene mutation assay, the V79 Chinese hamster cell mutagenesis assay, the chromosomal aberration assay in human lymphocytes in vitro, the mouse micronucleus assay in vivo, and the unscheduled DNA synthesis assay in primary rat hepatocytes in vitro.

In rats, decreases in the number of corpora lutea and the percentage of implants were noted at inhalation tiotropium doses of 78 mcg/kg/day or greater (approximately 35 times the RHDID on a mcg/m2 basis). No such effects were observed at 9 mcg/kg/day (approximately 4 times than the RHDID on a mcg/m2 basis). The fertility index; however, was not affected at inhalation doses up to 1689 mg/kg/day (approximately 760 times the RHDID on a mcg/m2 basis).

Olodaterol:

Two-year inhalation studies were conducted in rats and mice to assess the carcinogenic potential of olodaterol. Lifetime treatment of female rats induced leiomyomas of the mesovarium at doses of 25.8 and 270 mcg/kg/day (approximately 18- and 198-fold, respectively, the RHDID on an AUC basis). No tumor findings were observed in male rats at doses up to 270 mcg/kg/day (approximately 230-fold the RHDID on an AUC basis). Lifetime treatment of female mice induced leiomyomas and leiomyosarcomas of the uterus at doses ≥76.9 mcg/kg/day (approximately 106-fold the RHDID on an AUC basis). No tumor findings were observed in male mice at doses up to 255 mcg/kg/day (approximately 455-fold the RHDID on an AUC basis). Increases in leiomyomas and leiomyosarcomas of the female rodent reproductive tract have been similarly demonstrated with other beta2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Olodaterol was not mutagenic in the in vitro Ames test or in the in vitro mouse lymphoma assay. Olodaterol produced increased frequency of micronuclei in rats after intravenous doses. The increased frequency of micronuclei was likely related to drug enhanced (compensatory) erythropoiesis. The mechanism for induction of micronuclei formation is likely not relevant at clinical exposures.

Olodaterol did not impair male or female fertility in rats at inhalation doses up to 3068 mcg/kg/day (approximately 2322 times the RHDID on an AUC basis).

Clinical Studies

The safety and efficacy of tiotropium bromide and olodaterol were evaluated in a clinical development program that included three dose ranging trials, two active-controlled trials, three active- and placebo-controlled trials, and one placebo-controlled trial. The efficacy of tiotropium bromide and olodaterol is based primarily on two 4-week dose-ranging trials in 592 COPD patients and two confirmatory active-controlled 52-week trials (Trials 1 and 2) in 5162 COPD patients.

Dose-Ranging Trials

Dose selection for tiotropium bromide and olodaterol was primarily based on trials for the individual components, tiotropium bromide and olodaterol. Dose selection was also supported by two randomized, double-blind, active-controlled, 4-week trials. In one trial in 232 patients with COPD, three tiotropium doses (1.25, 2.5, and 5 mcg) were given in combination with olodaterol 5 or 10 mcg and were evaluated compared to olodaterol monotherapy. Results demonstrated improvement in trough FEV1 for the combination when compared to olodaterol alone. The difference in trough FEV1 for the tiotropium bromide/olodaterol doses of 1.25/5, 2.5/5, and 5/5 mcg once daily from olodaterol 5 mcg were 0.054 L (95% CI 0.016, 0.092), 0.065 L (0.027, 0.103), and 0.084 L (0.046, 0.122), respectively. In the second trial in 360 patients with COPD, three olodaterol doses (2, 5, and 10 mcg) were given in combination with tiotropium 5 mcg and were evaluated compared to tiotropium monotherapy. The difference in trough FEV1 for the tiotropium/olodaterol doses of 5/2, 5/5, and 5/10 mcg once daily from tiotropium 5 mcg were 0.024 L (95% CI -0.029, 0.076), 0.033 L (-0.019, 0.085), and 0.057 L (0.004, 0.110), respectively. Results of these trials supported the evaluation of once-daily doses of tiotropium bromide/olodaterol 2.5/5 mcg and 5/5 mcg in the confirmatory trials.

Confirmatory Trials:

A total of 5162 COPD patients (1029 receiving tiotropium bromide and olodaterol, 1038 receiving olodaterol 5 mcg, and 1033 receiving tiotropium bromide 5 mcg) were studied in two confirmatory trials of tiotropium bromide and olodaterol. Trials 1 and 2 were 52-week, replicate, randomized, double-blind, active controlled, parallel group trials that compared tiotropium bromide and olodaterol to tiotropium 5 mcg and olodaterol 5 mcg. In these trials, all products were administered via the RESPIMAT inhaler. The trials enrolled patients 40 years of age or older with a clinical diagnosis of COPD, a smoking history of more than 10 pack-years, and moderate to very severe pulmonary impairment (post-bronchodilator FEV1 less than 80% predicted normal [GOLD Stage 2-4]; post-bronchodilator FEV1 to FVC ratio of less than 70%). All treatments were administered once daily in the morning. The primary endpoints were changed from baseline in FEV1 AUC0-3hr and trough FEV1 after 24-weeks of treatment. The majority of the 5162 patients were male (73%), white (71%) or Asian (25%), with a mean age of 64.0 years. Mean post-bronchodilator FEV1 was 1.37 L (GOLD 2 [50%], GOLD 3 [39%], GOLD 4 [11%]). Mean beta2-agonist responsiveness was 16.6% of baseline (0.171 L). Pulmonary medications allowed as concomitant therapy included inhaled steroids [47%] and xanthines [10%].

In both Trials 1 and 2, tiotropium bromide and olodaterol demonstrated significant improvements in FEV1 AUC0-3hr and trough FEV1 after 24 weeks compared to tiotropium 5 mcg and olodaterol 5 mcg (Table 2). The increased bronchodilator effects of tiotropium bromide and olodaterol compared to tiotropium 5 mcg and olodaterol 5 mcg were maintained throughout the 52-week treatment period. Tiotropium bromide and olodaterol displayed a mean increase in FEV1 from baseline of 0.137 L (range: 0.133-0.140 L) within 5 minutes after the first dose. Patients treated with tiotropium bromide and olodaterol used less rescue medication compared to patients treated with tiotropium 5 mcg and olodaterol 5 mcg.

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For the subset of patients (n=521) who completed extended lung function measurements up to 12 hours post-dose, tiotropium bromide and olodaterol showed a significantly greater FEV1 response compared to tiotropium 5 mcg and olodaterol 5 mcg over the full 24-hour dosing interval. Results from Trial 2 are shown in Figure 1.

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How Supplied

The drug product, tiotropium bromide and olodaterol, is composed of a sterile aqueous solution of tiotropium bromide and olodaterol hydrochloride filled into a 4.5 mL plastic container crimped into an aluminum cylinder (tiotropium bromide and olodaterol cartridge) for use with the tiotropium bromide and olodaterol inhaler.

Excipients include water for injection, benzalkonium chloride, edetate disodium, and hydrochloric acid.

The tiotropium bromide and olodaterol cartridge is only intended for use with the tiotropium bromide and olodaterol inhaler. The tiotropium bromide and olodaterol inhaler is a hand held, pocket sized oral inhalation device that uses mechanical energy to generate a slow-moving aerosol cloud of medication from a metered volume of the drug solution. The tiotropium bromide and olodaterol inhaler has a light green-colored cap.

When used with the tiotropium bromide and olodaterol inhaler each cartridge, containing 4 grams of sterile aqueous solution, delivers the labeled number of metered actuations after preparation for use. Each dose (one dose equals two actuations) from the tiotropium bromide and olodaterol inhaler delivers 5 mcg tiotropium and 5 mcg olodaterol in 22.1 mcL from the mouthpiece. As with all inhaled drugs, the actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the inhaler and inspiration through the delivery system. The duration of inspiration should be at least as long as the spray duration (1.5 seconds).

Tiotropium bromide and olodaterol cartridge and one tiotropium bromide and olodaterol inhaler.

The tiotropium bromide and olodaterol cartridge is provided as an aluminum cylinder with a tamper protection seal on the cap. The tiotropium bromide and olodaterol cartridge is only intended for use with the tiotropium bromide and olodaterol inhaler and should not be interchanged with any other RESPIMAT device delivered product.

The tiotropium bromide and olodaterol inhaler is a cylindrical shaped plastic inhalation device with a gray colored body and a clear base. The clear base is removed to insert the cartridge. The inhaler contains a dose indicator. The light green-colored cap and the written information on the label of the gray inhaler body indicate that it is labeled for use with the tiotropium bromide and olodaterol cartridge.

Tiotropium Bromide and Olodaterol Inhalation Spray is available as: Tiotropium Bromide and Olodaterol Inhalation Spray: 60 metered actuations (NDC 0597-0155-61)

The tiotropium bromide and olodaterol cartridge has a net fill weight of at least 4 grams and when used with the tiotropium bromide and olodaterol inhaler, is designed to deliver the labeled number of metered actuations after preparation for use.

When the labeled number of actuations has been dispensed from the inhaler, the RESPIMAT locking mechanism will be engaged and no more actuations can be dispensed.

After assembly, the tiotropium bromide and olodaterol inhaler should be discarded at the latest 3 months after first use or when the locking mechanism is engaged, whichever comes first.

Keep out of reach of children. Do not spray into eyes.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Avoid freezing.

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Precautions with Alcohol

Alcohol-Tiotropium bromide and olodaterol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

STIOLTO RESPIMAT

Look-Alike Drug Names

There is limited information regarding Tiotropium bromide and olodaterol Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.